The present invention relates to a novel, orally-administrable sulfonyl derivative or salt thereof which inhibits an activated coagulation factor (which will hereinafter be abbreviated as xe2x80x9cFXaxe2x80x9d), thereby exhibiting strong anticoagulant action; and a coagulation suppressor or preventive and/or remedy for thrombosis or embolism which comprises the derivative or salt as an effective ingredient.
Exasperation of coagulation capacity is an important factor for unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger""s disease, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after valve replacement, reocclusion after revascularization or formation of thrombus upon extracorporeal circulation. There is accordingly a demand for an excellent anticoagulant which is excellent in dose-responsiveness, has long-lasting effects, has a low risk of hemorrhage, has less side effects and exhibits rapid and sufficient effects even by oral administration (Thrombosis Research, 68, 507-512, 1992).
Studies on anticoagulants based on various acting mechanisms suggest that a FXa inhibitor has a possibility of becoming an excellent anticoagulant. The coagulation system is a series of reactions wherein a large amount of a thrombus is produced through an amplification step due to a multi-stage enzymatic reaction and induces the formation of insoluble fibrin. In the intrinsic system, after the multi-stage reaction following the activation of a contact factor, activated Factor IX activates factor X on a phospholipid membrane in the presence of activated Factor VIII and a calcium ion, while in the extrinsic system, activated Factor VII activates Factor X in the presence of a tissue factor. In other words, the activation of Factor X into FXa in the coagulation system is an essential reaction in the formation of thrombin. Activated Factor X (FXa) in each system carries out limited proteolysis of prothrombin, thereby forming thrombin. The resulting thrombin activates the coagulation factors on the upstream side, whereby the formation of thrombin is amplified further. As described above, the coagulation system upstream of FXa is separated into intrinsic and extrinsic systems so that the inhibition of the enzyme of the coagulation system upstream of FXa does not suppress the production of FXa sufficiently, inevitably resulting in the production of thrombin. Furthermore, the coagulation occurs as a self-amplifying reaction so that the suppression of the coagulation system can be accomplished more efficiently by the inhibition of FXa which exists upstream of the thrombin than by the inhibition of the thrombin formed (Thrombosis Research, 15, 617-629(1979)).
Another merit of the FXa inhibitor is that an effective dose in a thrombus model is largely different from the dose for extending the bleeding time in an experimental hemorrhage model. From the experimental result, the FXa inhibitor is presumed to be an anticoagulant with a low risk of hemorrhage.
As a FXa inhibitor, various compounds are reported. In general, antithrombin III or antithrombin III-dependent penta-saccharide is known to have no inhibitory action against a prothrombinase complex which plays a practical role in the thrombus formation in vivo (Thrombosis Research, 68, 507-512(1992); Journal of Clinical Investigation, 71, 1383-1389(1983); Mebio, August issue, 1992-1997) and moreover, it does not exhibit effectiveness in oral administration. Although tick anticoagulant peptide (TAP) (Science, 248, 593-596(1990)) or antistacin (AST) (Journal of Biological Chemistry, 263, 10162-10167(1988)) isolated from a tick or leech which is a bloodsucker inhibits FXa and exhibits anti-thrombus effects on the models of from venous thrombus to arterial thrombus, it is not effective when orally administered because it is a high-molecular peptide. From such a viewpoint, a low-molecular FXa inhibitor which directly inhibits a coagulation factor without depending on antithrombin III has been developed.
An object of the present invention is to provide, as an excellent anticoagulant, a novel compound which has strong FXa inhibitory action, exhibits prompt, sufficient and long-lasting anti-thrombus effects even by the oral administration and has less side effects.
With the forgoing in view, the present inventors have carried out an extensive investigation on the synthesis of a novel FXa inhibitor and its pharmacological action. As a result, it has been found that a novel sulfonyl derivative, salt thereof or solvate thereof exhibits strong FXa inhibitory action and strong anticoagulant action, inhibits FXa strongly, promptly and continuously by the oral administration, exhibits anti-coagulant action and anti-thrombus action, is highly safe and is useful as a preventive or remedy for various diseases caused by a thrombus or embolus, thus leading to completion of the present invention. The present invention provides a sulfonyl derivative represented by the following formula (I): 
[wherein:
R1 represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyl group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkylcarbonyloxy group or a group A1-B1xe2x80x94 (in which A1 represents an amino group which may have one or two substituents, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B1 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group),
R2 and R3 each independently represents a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group or an alkoxyalkyl group or R2 or R3 may be coupled together with R1 to form a C1-3 alkylene or alkenylene group,
R4 and R5 each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group or an alkoxyl group (with the proviso that R4 and R5 do not represent a hydrogen atom at the same time),
Q1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a saturated or unsaturated bicyclic or tricyclic fused ring group which may have a substituent,
Q2 represents a single bond, an oxygen atom, a sulfur atom, a linear or branched C1-6 alkylene group, a linear or branched C2-6 alkenylene group, a linear or branched C2-6 alkynylene group, a group xe2x80x94N(R6)xe2x80x94COxe2x80x94 (in which R6 represents a hydrogen atom or an alkyl group), a group xe2x80x94N(R7)xe2x80x94(CH2)mxe2x80x94 (in which R7 represents a hydrogen atom or an alkyl group and m stands for an integer of 0 to 6) or a group of the following formula: 
xe2x80x83(which represents a divalent, saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a divalent, saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent or a divalent, saturated or unsaturated dicyclic fused ring group which may have a substituent and ←C means the bonding of the carbon atom of this group to Q1),
Q3 represents any one of the following groups: 
xe2x80x83(in which when the carbon atom to which each of R8, R9, R10, R11, R12, R13, R15 and R16 has been bonded is not adjacent to a nitrogen atom, R8, R9, R10, R11, R12, R13, R15 and R16 each independently represents:
a hydrogen atom,
a hydroxyl group,
an alkyl group,
an alkoxyl group,
an alkoxyalkyl group,
an alkoxyalkyloxy group,
a hyroxyalkyl group,
a hydroxyalkyloxy group,
a hydroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
a formylalkylsulfonyl group,
an alkylcarbonyl group,
an alkylsulfonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonylalkyl group,
a carboxyl group,
a carboxyalkyl group,
a carboxyalkyloxy group,
a carboxyalkylcarbonyl group,
a carboxyalkylsulfonyl group,
a carboxyalkylcarbonylalkyl group,
a carboxyalkylsulfonylalkyl group ,
an alkoxycarbonyl group,
an alkoxycarbonylalkyl group,
an alkoxycarbonylalkyloxy group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
an amino group which may have one or two substituents,
an aminoalkyl group in which the amino moiety may have one or two substituents,
an aminoalkyloxy group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyloxy group in which the amino moiety may have one or two substituents,
an aminocarbonyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyloxy group in which the amino moiety may have one or two substituents or
a group A2-B2xe2x80x94 (in which A2 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B2 represents a single bond, a carbonyl group or an alkylene group),
when the carbon atom to which each of R8, R9, R10, R11, R12 , R13, R15 and R16 has been bonded is adjacent to a nitrogen atom, R8, R9, R10, R11, R12, R13, R15 and R16 each independently represents:
a hydrogen atom,
an alkyl group,
a hydroxyalkyl group,
a hydroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
a formylalkylsulfonyl group,
an alkylcarbonyl group,
an alkylsulfonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonylalkyl group,
a carboxyl group,
a carboxyalkyl group,
a carboxyalkylcarbonyl group,
a carboxyalkylsulfonyl group,
a carboxyalkylcarbonylalkyl group,
a carboxyalkylsulfonylalkyl group,
an alkoxyalkyl group,
an alkoxycarbonyl group,
an alkoxycarbonylalkyl group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
an aminoalkyl group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,
an aminocarbonyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyl group in which the amino moiety may have one or two substituents or
a group A3-B3xe2x80x94 (in which A3 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and B3 represents a single bond, a carbonyl group or an alkylene group),
R8 and R9, R10 and R11, R12 and R13, and R15 and R16 may each be coupled together with a carbon atom which constitutes the ring and represent a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent,
R14 and R17 each independently represents:
a hydrogen atom,
an alkyl group,
a hydroxyalkyl group,
a hydroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
an alkoxyl group,
an alkoxyalkyl group,
an alkoxyalkylcarbonyl group,
an alkoxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
a formylalkylsulfonyl group,
an aklylcarbonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonyl group,
an alkylsulfonylalkyl group,
a carboxyalkyl group,
a carboxyalkylcarbonyl group,
a carboxyalkylsulfonyl group,
a carboxyalkylcarbonylalkyl group,
a carboxyalkylsulfonylalkyl group,
an alkoxycarbonyl group,
an alkoxycarbonylalkyl group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
an amino group which may have one or two substituents,
an aminoalkyl group in which the amino moiety may have one or two substituents,
an aminoalkyloxy group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,
an aminoalkyloxycarbonyl group in which the amino moiety may have one or two substituents,
an aminocarbonyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyl group in which the amino moiety may have one or two substituents,
an aminocarbonyloxyalkyl group in which the amino moiety may have one or two substituents,
R14 and R12 or R13 may be coupled together with a carbon
atom constituting the ring and a nitrogen atom to which R14 has been bonded and represent a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent,
R17 and R15 or R16 may be coupled together with a carbon atom constituting the ring and a nitrogen atom to which R17 has been bonded and represent a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent,
a, b, d, e and g each independently stands for an integer of 0 or 1, c stands for an integer of 0 to 3, f, h and i each independently represents an integer of 1 to 3, with the proviso that the sum of a, b and c stands for an integer of 2 or 3, the sum of d and e stands for an integer of 0 or 1 and the sum of f, g and h stands for an integer of 3 to 5),
T1 represents a carbonyl group, a group xe2x80x94CH(R18)xe2x80x94 (in which R18 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group in which the amino moiety may have a substituent) or a group xe2x80x94C(xe2x95x90NOR19)xe2x80x94 (in which R19 represents a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group in which the amino moiety may have a substituent, and
X1 and X2 each independently represents a methine group or a nitrogen atom]; salt thereof; or solvate thereof.
The present invention also provides a medicament comprising as an effective ingredient a sulfonyl derivative represented by the formula (1), salt thereof or solvate thereof.
The present invention also provides a pharmaceutical composition comprising a sulfonyl derivative represented by the formula (1), salt thereof or solvate thereof; and a pharmaceutically acceptable carrier.
The present invention also provides the use of a sulfonyl derivative represented by the formula (1), salt thereof or solvate thereof as a medicament.
The present invention also provides a method for treating a disease caused by thrombosis or embolism, which comprises administering, to a patient suffering therefrom, a sulfonyl derivative represented by the formula (1), salt thereof or solvate thereof.
A description will next be made of the substituents in the sulfonyl group derivative of the formula (I) according to the present invention.
As R1, examples of the halogen atom include fluorine, chlorine, bromine and iodine.
Examples of the alkyl group include linear, branched or cyclic C1-6 alkyl groups such as methyl, ethyl, isopropyl and cyclopropyl.
The xe2x80x9chydroxyalkyl groupxe2x80x9d means a group formed of a hydroxyl group and a linear, branched or cyclic C1-6 alkylene group. Examples of the alkylene group include methylene, ethylene, trimethylene, propylene and cyclohexylene. Examples of the hydroxyalkyl group include hydroxymethyl and hydroxyethyl.
The xe2x80x9calkoxyl groupxe2x80x9d means a group formed of the above-described C1-6 alkyl group and an oxygen atom. Examples include methoxyl, ethoxyl and isopropoxyl.
The xe2x80x9calkoxyalkyl groupxe2x80x9d means a group formed of the above-described alkoxyl group and the above-described C1-6 alkylene group. Examples include methoxymethyl, methoxyethyl and ethoxymethyl.
The xe2x80x9ccarboxyalkyl groupxe2x80x9d means a group formed of a carboxyl group and the above-described C1-6 alkylene group. Examples include carboxymethyl and carboxyethyl.
The xe2x80x9calkylcarbonyl groupxe2x80x9d means a group formed of the above-described C1-6 alkyl group and a carbonyl group. Examples include methylcarbonyl and ethylcarbonyl.
The xe2x80x9calkoxycarbonyl groupxe2x80x9d means a group formed of the above-described C1-6 alkoxyl group and a carbonyl group. Examples include methoxycarbonyl and ethoxycarbonyl.
The xe2x80x9calkoxycarbonylalkyl groupxe2x80x9d means a group formed of the above-described alkoxycarbonyl group and the above-described alkylene group. Examples include methoxycarbonylethyl and ethoxycarbonylmethyl.
The xe2x80x9calkylcarbonyloxy groupxe2x80x9d means a group formed of the above-described C1-6 alkyl group, a carbonyl group and an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy and isopropylcarbonyloxy.
In the group A1-B1xe2x80x94, A1 represents an amino group which may have one or two substituents, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent.
When A1 represents an amino group which may have one or two substituents, B1 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group. The group A1-B1xe2x80x94 therefore represents, for example, a group as shown in the following class (A).
Class (A):
an amino group which may have one or two substituents,
an aminocarbonyl group in which the amino moiety may have one or two substituents,
an aminoalkyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyloxy group in which the amino moiety may have one or two substituents or
an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents and
an aminoalkylcarbonyloxy group in which the amino moiety may have one or two substituents.
A description will next be made of the groups shown in Class (A).
The xe2x80x9caminocarbonyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of an amino group which may have one or two substituents and a carbonyl group.
The xe2x80x9caminoalkyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of an amino group which may have one or two substituents and the above-described C1-6 alkylene group. Examples of the aminoalkyl group include aminomethyl and aminoethyl.
The xe2x80x9caminocarbonylalkyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminocarbonyl group and the above-described C1-6 alkylene group. Examples of the aminocarbonylalkyl group include aminocarbonylmethyl and aminocarbonylethyl.
The xe2x80x9caminocarbonylalkyloxy group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminocarbonylakyl group and an oxygen atom. Examples of the aminocarbonylalkyloxy group include aminocarbonylmethoxyl and aminocarbonylethoxyl.
The xe2x80x9caminoalkylcarbonyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminoalkyl group and a carbonyl group. Examples of the aminoalkylcarbonyl group include aminomethylcarbonyl and aminoethylcarbonyl.
The xe2x80x9caminoalkylcarbonyloxy group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminoalkylcarbonyl group and an oxygen atom. Examples of the aminoalkylcarbonyloxy group include aminomethylcarbonyloxy and aminoethylcarbonyloxy.
Examples of the substituent which can be substituted for an amino group include those as shown in the following Class, (1).
Class (1):
an alkyl group,
an alkenyl group,
a halogenoalkyl group,
a halogenoalkenyl group,
a hydroxyalkyl group,
a hyroxyalkylcarbonyl group,
a hydroxyalkylsulfonyl group,
an alkoxyl group,
an alkoxyalkyl group,
an alkoxyalkylcarbonyl group,
an alkoxyalkylsulfonyl group,
a formyl group,
a formylalkyl group,
a formylalkylcarbonyl group,
a formylalkylsulfonyl group,
an alkylcarbonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonyl group,
an alkylsulfonylalkyl group,
a carboxyalkyl group,
a carboxyalkylcarbonyl group,
a carboxyalkylsulfonyl group,
a carboxyalkylcarbonylalkyl group,
a carboxyalkylsulfonylalkyl group,
an alkoxycarbonyl group,
an alkoxycarbonylalkyl group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
a trifluoromethylsulfonyloxyalkenyl group and
a group a1-b1xe2x80x94 (wherein a1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or saturated or unsaturated 5- or 6-membered heterocyclic group which may have one to three substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group and an aminocarbonyl group; and
b1represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group, an alkylenecarbonyloxy group, an alkyleneaminocarbonyl group, an alkyleneaminocarbonylalkyl group, an alkyleneaminosulfonyl group or an alkyleneaminosulfonylalkyl group).
The substituents which can be substituted for an amino group in Class (1) will next be described.
The alkyl group has the same meaning as described above.
The xe2x80x9calkenyl groupxe2x80x9d means a linear, branched or cyclic C2-6 alkenyl group. Examples include vinyl and allyl.
The xe2x80x9chalogenoalkyl groupxe2x80x9d means a group formed of a halogen atom and the above-described alkylene group. Examples include chloromethyl and bromoethyl.
The xe2x80x9chalogenoalkenyl groupxe2x80x9d means a group formed of a halogen atom and a linear or branched C2-6 alkenylene group. Examples include chloroethenyl and bromopropenyl groups. There is no particular limitation on the position of a double bond.
The xe2x80x9chydroxyalkyl groupxe2x80x9d means a group formed of a hydroxyl group and a linear, branched or cyclic C2-6 alkylene group. Examples include hydroxyethyl and hydroxypropyl.
The xe2x80x9chydroxyalkylcarbonyl groupxe2x80x9d means a group formed of the above-described hydroxyalkyl group and a carbonyl group. Examples include hydroxymethylcarbonyl and hydroxyethylcarbonyl.
The xe2x80x9chydroxyalkylsulfonyl groupxe2x80x9d means a group formed of the above-described hydroxyalkyl group and a sulfonyl group. Examples include hydroxymethylsulfonyl and hydroxyethylsulfonyl.
The alkoxyl group has the same meaning as described above.
The xe2x80x9calkoxyalkyl groupxe2x80x9d means a group formed of the above-described alkoxyl group and linear, branched or cyclic C2-6 alkylene group. Examples include methoxyethyl, ethoxyethyl and methoxypropyl.
The xe2x80x9calkoxyalkylcarbonyl groupxe2x80x9d means a group formed of the above-described alkoxyalkyl group and a carbonyl group. Examples include methoxyethylcarbonyl and ethoxymethylcarbonyl.
The xe2x80x9calkoxyalkylsulfonyl groupxe2x80x9d means a group formed of the above-described alkoxyalkyl group and a sulfonyl group. Examples include methoxymethylsulfonyl and ethoxymethylsulfonyl.
The xe2x80x9cformylalkyl groupxe2x80x9d means a group formed of a formyl group and the above-described C1-6 alkylene group. Examples include formylmethyl and formylethyl.
The xe2x80x9cformylalkylcarbonyl groupxe2x80x9d means a group formed of the above-described formylalkyl group and a carbonyl group. Examples include formylmethylcarbonyl and formylethylcarbonyl.
The xe2x80x9cformylalkylsulfonyl groupxe2x80x9d means a group formed of the above-described formylalkyl group and a sulfonyl group. Examples include formylmethylsulfonyl and formylethylsulfonyl.
The xe2x80x9calkylcarbonyl groupxe2x80x9d means a group formed of the above-described alkyl group and a carbonyl group. Examples include methylcarbonyl and ethylcarbonyl.
The xe2x80x9calkylcarbonylalkyl groupxe2x80x9d means a group formed of the above-described alkylcarbonyl group and the above-described C1-6 alkylene group. Examples include methylcarbonylmethyl and ethylcarbonylmethyl.
The xe2x80x9calkylsulfonyl groupxe2x80x9d means a group formed of the above-described alkyl group and a sulfonyl group. Examples include methylsulfonyl and ethylsulfonyl.
The xe2x80x9calkylsulfonylalkyl groupxe2x80x9d means a group formed of the above-described alkylsulfonyl group and the above-described C1-6 alkylene group. Examples include methylsulfonylmethyl and ethylsulfonylmethyl.
The carboxyalkyl group has the same meaning as described above.
The xe2x80x9ccarboxyalkylcarbonyl groupxe2x80x9d means a group formed of the above-described carboxyalkyl group and a carbonyl group. Examples include carboxymethylcarbonyl and carboxyethylcarbonyl.
The xe2x80x9ccarboxyalkylsulfonyl groupxe2x80x9d means a group formed of the above-described carboxyalkyl group and a sulfonyl group. Examples include carboxymethylsulfonyl and carboxyethylsulfonyl.
The xe2x80x9ccarboxyalkylcarbonylalkyl groupxe2x80x9d means a group formed of the above-described carboxyalkylcarbonyl group and the above-described C1-6 alkylene group. Examples include carboxymethylcarbonylmethyl and carboxyethylcarbonylmethyl.
The xe2x80x9ccarboxyalkylsulfonylalkyl groupxe2x80x9d means a group formed of the above-described carboxyalkylsulfonyl group and the above-described C1-6 alkylene group. Examples include carboxymethylsulfonylmethyl and carboxyethylsulfonylmethyl.
The alkoxycarbonyl and alkoxycarbonylalkyl groups have the same meanings as described above.
The xe2x80x9calkoxycarbonylalkylcarbonyl groupxe2x80x9d means a group formed of the above-described alkoxycarbonylalkyl group and a carbonyl group. Examples include methoxycarbonylethylcarbonyl and ethoxycarbonylmethylcarbonyl.
The xe2x80x9calkoxycarbonylalkylsulfonyl groupxe2x80x9d means a group of the above-described alkoxycarbonylalkyl group and a sulfonyl group. Examples include methoxycarbonylethylsulfonyl and ethoxycarbonylmethylsulfonyl.
The xe2x80x9ctrifluoromethylsulfonyloxyalkenyl groupxe2x80x9d means a group formed of a trifluoromethylsulfonyloxy group and a linear or branched C2-6 alkenylene group. Examples include trifluoromethylsulfonyloxyvinyl and trifluoromethylsulfonyloxyallyl.
In the group a1-b1xe2x80x94, a1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent such as a halogen atom. Examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. Where the group has, as the cyclopentenyl, plural structural isomers, it is to be noted that they are all embraced in it.
The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one hetero atom. Examples of the hetero atom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. Where the group has, as the pyranyl, plural structural isomers, it is to be noted that they are all embraced in it.
b1 represents a single bond or a carbonyl, alkylene, carbonylalkyl, carbonylalkyloxy, alkylenecarbonyloxy, alkyleneaminocarbonyl, alkyleneaminocarbonylalkyl, alkyleneaminosulfonyl or alkyleneaminosulfonylalkyl group. The alkylene group has the same meaning as described above.
The xe2x80x9ccarbonylalkyl groupxe2x80x9d means a group formed of a carbonyl group and the above-described C1-6 alkylene group. Examples include carbonylmethyl and carbonylethyl.
The xe2x80x9ccarbonylalkyloxy groupxe2x80x9d means a group formed of the above-described carbonylalkyl group and an oxygen atom. Examples include carbonylmethoxy and carbonylethoxy.
The xe2x80x9calkylenecarbonyloxy groupxe2x80x9d means a group formed of the above-described C1-6 alkylene group, a carbonyl group and an oxygen atom. Examples include methylenecarbonyloxy and ethylenecarbonyloxy.
The xe2x80x9calkyleneaminocarbonyl groupxe2x80x9d means a group formed of the above-described C1-6 alkylene group, an imino group and a carbonyl group. Examples include methyleneaminocarbonyl and ethyleneaminocarbonyl.
The xe2x80x9calkyleneaminocarbonylalkyl groupxe2x80x9d means a group formed of the above-described alkyleneaminocarbonyl and the above-described C1-6 alkylene. Examples include methyleneaminocarbonylmethyl and ethyleneaminocarbonylmethyl.
The xe2x80x9calkyleneaminosulfonyl groupxe2x80x9d means a group formed of the above-described C1-6 alkylene group, an imino group and a sulfonyl group. Examples include methyleneaminosulfonyl and ethyleneaminosulfonyl.
The xe2x80x9calkyleneaminosulfonylalkyl groupxe2x80x9d means a group formed of the above-described alkyleneaminosulfonyl and the above-described C1-6 alkylene. Examples include methyleneaminosulfonylmethyl and ethyleneaminosulfonylmethyl.
A description will next be made of the substituents which can be introduced to, as the above-described a1, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. The alkoxyl, alkyl, alkoxycarbonyl and aminocarbonyl groups have the same meanings as described above.
As the group a1-b1xe2x80x94, there exist various kinds according to the combination of a1 and b1. Examples include:
a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent,
a group formed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and a carbonyl group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and an alkylene group,
a group formed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and a carbonylalkyl group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and a carbonylalkyloxy group,
a group formed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and a alkylenecarbonyloxy group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and a alkyleneaminocarbonyl group,
a group formed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and an alkyleneaminocarbonylalkyl group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and an alkyleneaminosulfonyl group,
a group formed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and an alkyleneaminosulfonylalkyl group and the like.
In addition to the above-described Class (1), the following Class (2) can be given as examples of the substituent which can be substituted for the amino group.
Class (2):
an amino group which may have one or two substituents selected from Class (1),
an aminoalkyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminocarbonyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminocarbonylalkyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminocarbonylalkylcarbonyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminocarbonylalkylsulfonyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminosulfonyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminosulfonylalkyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminoalkylsulfonyl group in which the amino moiety may have one or two substituents selected from Class (1),
an aminosulfonylalkylcarbonyl group in which the amino moiety may have one or two substituents selected from Class (1) and
an aminosulfonylalkylsulfonyl group in which the amino moiety may have one or two substituents selected from Class (1).
A description will next be made of the substituents of Class (2).
The aminocarbonyl, aminocarbonylalkyl and aminoalkylcarbonyl groups in Class (2) have the same meanings as described above.
The xe2x80x9caminoalkyl group which may have a substituentxe2x80x9d means a group formed of an amino group which may have a substituent and a linear, branched or cyclic C2-6 alkylene group. Examples of the aminoalkyl group include aminoethyl and aminopropyl.
The xe2x80x9caminocarbonylalkylcarbonyl group which may have a substituentxe2x80x9d means a group formed of an aminocarbonylalkyl group which may have a substituent and a carbonyl group. Examples of the aminocarbonylalkylcarbonyl group include aminocarbonylmethylcarbonyl and aminocarbonylethylcarbonyl.
The xe2x80x9caminocarbonylalkylsulfonyl group which may have a substituentxe2x80x9d means a group formed of an aminocarbonylalkyl group which may have a substituent and a sulfonyl group. Examples of the aminocarbonylalkylsulfonyl group include aminocarbonylmethylsulfonyl and aminocarbonylethylsulfonyl.
The xe2x80x9caminosulfonyl group which may have a substituentxe2x80x9d means a group formed of an amino group which may have a substituent and a sulfonyl group.
The xe2x80x9caminosulfonylalkyl group which may have a substituentxe2x80x9d means a group formed of the above-described aminosulfonyl group which may have a substituent and the above-described C1-6 alkylene group. Examples of the aminosulfonylalkyl group include aminosulfonylmethyl and aminosulfonylethyl.
The xe2x80x9caminoalkylsulfonyl group which may have a substituentxe2x80x9d means a group formed of the above-described amino group which may have a substituent, the above-described C1-6 alkylene group and a sulfonyl group. Examples of the aminoalkylsulfonyl group include aminomethylsulfonyl and aminoethylsulfonyl.
The xe2x80x9caminosulfonylalkylcarbonyl group which may have a substituentxe2x80x9d means a group formed of the above-described aminosulfonylalkyl group which may have a substituent and a carbonyl group. Examples include aminosulfonylmethylcarbonyl and aminosulfonylethylcarbonyl.
The xe2x80x9caminosulfonylalkylsulfonyl group which may have a substituentxe2x80x9d means a group formed of the above-described aminosulfonylalkyl group which may have a substituent and a sulfonyl group. Examples include aminosulfonylmethylsulfonyl and aminosulfonylethylsulfonyl.
A1 also represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent. Examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl groups. Where the group has plural structural isomers as the cyclopentenyl group, it is to be noted that they are all embraced in it.
The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one hetero atom. Examples of the hetero atom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, triazolyl and triazinyl. Where the group has plural structural isomers as pyranyl, it is to be noted that they are all embraced in it.
When A1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, B1 represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group. Accordingly, the group A1-B1xe2x80x94, for example, represents a group as shown in the following Class (B):
Class (B):
a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent and a carbonyl group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent and an alkylene group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, a carbonyl group and an alkylene group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, a carbonyl group, an alkylene group and an oxygen atom,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, an alkylene group and a carbonyl group,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, an alkylene group, a carbonyl group and an oxygen atom, and the like.
A description will next be made of the groups shown in Class (B).
In the group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent and a carbonyl group, examples of the group formed of the cyclic hydrocarbon group and a carbonyl group include cyclopentylcarbonyl and phenylcarbonyl; while those of the group formed of the heterocyclic group and a carbonyl group include furylcarbonyl, thienylcarbonyl and pyridylcarbonyl groups.
In the group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent and an alkylene group, the xe2x80x9cgroup formed of a cyclic hydrocarbon group and an alkylene groupxe2x80x9d means a group formed of the above-described cyclic hydrocarbon group and the above-described C1-6 alkylene group, for example, cyclohexylmethyl and benzyl, while the xe2x80x9cgroup formed of a heterocyclic group and an alkylene groupxe2x80x9d means a group formed of the above-described heterocyclic group and the above-described C1-6 alkylene group, for example, furylmethyl, thienylethyl and pyridylpropyl.
In the group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, a carbonyl group and an alkylene group, the xe2x80x9cgroup formed of a cyclic hydrocarbon group, a carbonyl group and an alkylene groupxe2x80x9d means a group formed of the above-described cyclic hydrocarbon group, a carbonyl group and the above-described C1-6 alkylene group, for example, cyclopentadienylcarbonylmethyl and phenylcarbonylethyl, while the xe2x80x9cgroup formed of a heterocyclic group, a carbonyl group and an alkylene groupxe2x80x9d means a group formed of the above-described heterocyclic group, a carbonyl group and the above-described C1-6 alkylene group, for example, furylcarbonylmethyl, thienylcarbonylethyl and pyridylcarbonylpropyl.
In the group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, a carbonyl group, an alkylene group and an oxygen atom, the xe2x80x9cgroup formed of a cyclic hydrocarbon group, a carbonyl group, an alkylene group and an oxygen atomxe2x80x9d means a group composed of the above-described group, which is formed of a cyclic hydrocarbon group, a carbonyl group and an alkylene group, and an oxygen atom, for example, cyclopentylcarbonylmethoxy and phenylcarbonylethoxy, while the xe2x80x9cgroup formed of a heterocyclic group, a carbonyl group, an alkylene group and an oxygen atomxe2x80x9d means a group composed of the above-described group, which is formed of a heterocyclic group, a carbonyl group and an alkylene group, and an oxygen atom, for example, furylcarbonylmethoxy, thienylcarbonylethoxy and pyridylcarbonylpropoxy.
In the group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, an alkylene group and a carbonyl group, xe2x80x9cthe group formed of a cyclic hydrocarbon group, an alkylene group and a carbonyl groupxe2x80x9d means a group composed of the above-described group, which is formed of a cyclic hydrocarbon group and an alkylene group, and a carbonyl group, for example, cyclohexylmethylcarbonyl and phenylethylcarbonyl, while xe2x80x9cthe group formed of a heterocyclic group, an alkylene group and a carbonyl groupxe2x80x9d means a group composed of the above-described group, which is formed of a heterocyclic group and an alkylene group, and a carbonyl group, for example, furylmethylcarbonyl, thienylethylcarbonyl and pyridylpropylcarbonyl.
In the group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, an alkylene group, a carbonyl group and an oxygen atom, xe2x80x9cthe group formed of a cyclic hydrocarbon group, an alkylene group, a carbonyl group and an oxygen atomxe2x80x9d means a group composed of the above-described group, which is formed of a cyclic hydrocarbon group, an alkylene group and a carbonyl group, and an oxygen atom, for example, cyclohexadienylmethylcarbonyloxy and phenylethylcarbonylyoxy, while xe2x80x9cthe group formed of a heterocyclic group, an alkylene group, a carbonyl group and an oxygen atomxe2x80x9d means a group composed of the above-described group, which is formed of a heterocyclic group, an alkylene group and a carbonyl group, and an oxygen atom such as furylmethylcarbonyloxy, thienylethylcarbonyloxy and pyridylpropylcarbonyloxy.
As examples of a substituent which can be substituted for the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group, those as shown in Class (3) can be given.
Class (3):
a hydroxyl group,
an alkyl group,
an alkoxyl group,
a hydroxyalkyl group,
an alkoxyalkyl group,
a halogen atom,
a cyano group,
a nitro group,
a carboxyl group,
an alkoxycarbonyl group,
a formyl group,
a heteroaryl group,
a heteroarylalkyl group,
an alkylimino group,
an amidino group,
a guanidino group,
an amino(hydroxyimino)alkyl group,
an amino(alkoxyimino)alkyl group,
an amino(aryloxyimino)alkyl group,
an amino group which may have one or two substituents,
an aminocarbonyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyloxy group in which the amino moiety may have one or two substituents,
an aminoalkyl group in which the amino moiety may have one or two substituents,
an aminoalkyloxy group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyloxy group in which the amino moiety may have one or two substituents, and
an oxygen atom.
The number of the replaceable substituents ranges from 1 to 3.
A description will next be made of the substituents which can be substituted for the saturated or unsaturated 5- or 6-membered heterocyclic group in Class (3).
The alkyl group, alkoxyl group, hydroxyalkyl group, alkoxyalkyl group, halogen atom, alkoxycarbonyl group have the same meanings as described above in R1.
The xe2x80x9cheteroaryl groupxe2x80x9d means a monovalent aromatic group having at least one hetero atom. Examples include pyridyl, furyl and thienyl.
The xe2x80x9cheteroarylalkyl groupxe2x80x9d means a group formed of the above-described heteroaryl group and the above-described C1-6 alkylene group. Examples include pyridylmethyl, furylethyl and thienylmethyl.
The xe2x80x9calkylimino groupxe2x80x9d means a group formed of the above-described alkyl group and a nitrogen atom. Examples include methylimino and ethylimino.
The xe2x80x9camino(hydroxyimino)alkyl groupxe2x80x9d means a group in which amino and hydroxyimino groups have been bonded to the same carbon atom of the above-described alkyl group. Examples include amino(hydroxyimino)methyl and amino(hydroxyimino)ethyl.
The xe2x80x9camino(alkoxyimino)alkyl groupxe2x80x9d means a group in which amino and alkoxyimino groups have been bonded to the same carbon atom of the above-described alkyl group. Here, the xe2x80x9calkoxyimino groupxe2x80x9d means a divalent group formed of the above-described alkoxyl group and an imino group. Examples of the amino(alkoxyimino)alkyl group include amino(methoxyimino)methyl and amino(ethoxyimino)methyl.
The xe2x80x9camino(aryloxyimino)alkyl groupxe2x80x9d means a group in which amino and aryloxyimino groups have been bonded to the same carbon atom of the above-described alkyl group. Here, the xe2x80x9caryloxyimino groupxe2x80x9d means a divalent group formed of aryl and imino groups. Examples of the aryl group include phenyl, naphthyl, anthryl and phenanthryl. Examples of the amino(aryloxyimino)alkyl group include amino(phenoxyimino)methyl and amino(naphthyloxyimino)methyl.
The xe2x80x9caminocarbonyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of an amino group which may have one or two substituents and a carbonyl group.
The xe2x80x9caminoalkyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of an amino group which may have one or two substituents and the above-described C1-6 alkylene group. Examples of the aminoalkyl group include aminomethyl and aminoethyl.
The xe2x80x9caminocarbonylalkyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminocarbonyl group in which the amino moiety may have one or two substituents and the above-described C1-6 alkylene group. Examples of the aminocarbonylalkyl group include aminocarbonylmethyl and aminocarbonylethyl.
The xe2x80x9caminocarbonylalkyloxy group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminocarbonylalkyl group in which the amino moiety may have one or two substituents and an oxygen atom. Examples of the aminocarbonylalkyloxy group include aminocarbonylmethoxyl and aminocarbonylethoxyl.
The xe2x80x9caminoalkylcarbonyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminoalkyl group in which the amino moiety may have one or two substituents and a carbonyl group. Examples of the aminoalkylcarbonyl group include aminomethylcarbonyl and aminoethylcarbonyl.
The xe2x80x9caminoalkylcarbonyloxy group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described aminoalkylcarbonyl group in which the amino moiety may have one or two substituents and an oxygen atom. Examples of the aminoalkylcarbonyloxy group include aminomethylcarbonyloxy and aminoethylcarbonyloxy.
The xe2x80x9caminoalkyloxy group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of an amino group which may have a substituent, a linear, branched or cyclic C2-6 alkylene group and an oxygen atom. Examples of the aminoalkyloxy group include aminoethyloxy and aminopropyloxy.
In the case of the cyclic hydrocarbon group, an oxygen atom can serve as a substituent when the corresponding keto compound is formed, while, in the case of the heterocyclic group or dicyclic or tricyclic fused ring group, an oxygen atom can serve as a substituent when the oxygen atom is bonded to a nitrogen or sulfur atom forming the ring and the corresponding N-oxide or S-oxide or keto compound is formed.
In the present invention, when R1 is not coupled with R2 or R3 to form a C1-3 alkylene or alkenylene group, preferred examples of R1 include a hydrogen atom, an alkyl group, a hydroxyalkyl group and a group A1-B1xe2x80x94.
In R2 and R3, examples of the halogen atom include fluorine, chlorine, bromine and iodine.
The xe2x80x9calkyl groupxe2x80x9d means a linear, branched or cyclic C1-8 alkyl group. Examples include methyl, ethyl, isopropyl, cyclopropyl, heptyl and octyl.
The xe2x80x9chydroxyalkyl groupxe2x80x9d means a group formed of a hydroxyl group and a linear, branched or cyclic C1-8 alkylene group. Examples include hydroxymethyl and hydroxyethyl.
The xe2x80x9calkoxyalkyl groupxe2x80x9d means a group formed of the above-described alkyl group, an oxygen atom and a linear, branched or cyclic C1-8 alkylene group. Examples include methoxymethyl, methoxyethyl and ethoxymethyl.
When R2 or R3 is coupled with R1 to form a C1-3 alkylene or alkenylene group, the following group, in the formula (I): 
means the below-described group or the like. 
In the present invention, when R2 or R3 is not coupled with R1 to form a C1-3 alkylene or alkenylene group, a hydrogen atom and alkyl group are preferred as R2 or R3.
In the present invention, it is preferred that R1 and R2 or R3 are coupled together to form a C1-3 alkylene or alkenylene group.
In R4 or R5, examples of the halogen atom include fluorine, chlorine, bromine and iodine. The alkyl and alkoxyl groups have the same meanings as described above in R1. In the present invention, as R4 or R5, a halogen atom is preferred, with fluorine, chlorine and bromine being particularly preferred.
Q1 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent,
a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, or
a saturated or unsaturated, dicyclic or tricyclic fused ring group which may have a substituent.
Here, examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has plural structural isomers as cyclopentenyl, it is to be noted that they are all embraced in it.
The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one hetero atom. Examples of the hetero atom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, triazolyl and triazinyl. Where the group has plural structural isomers as pyranyl, it is to be noted that they are all embraced in it.
The xe2x80x9csaturated or unsaturated, dicyclic or tricyclic fused ring group which may have a substituentxe2x80x9d means: {circle around (1)} a group obtained by the condensation of the above-described saturated or unsaturated 5- or 6-membered cyclic hydrocarbon groups which may have a substituent, {circle around (2)} a group obtained by the condensation of the above-described saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and the above-described saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and {circle around (3)} a group obtained by the condensation of the above-described saturated or unsaturated 5- or 6-membered heterocyclic groups which may have a substituent. Examples of the group {circle around (1)} include indenyl, indanyl, naphthyl, tetrahydronaphthyl, anthryl and phenanthryl; those of the group {circle around (2)} include benzofuranyl, indolyl, indolinyl, quinolyl, benzodiazinyl and tetrahydroisoquinolyl; and those of the group {circle around (3)} include naphthyridinyl, tetrahydrothienopyridyl, tetrahydrothiazolopyridyl and tetrahydropyridinopyridyl.
Examples of the substituent which can be substituted for the above-described cyclic hydrocarbon, heterocyclic, dicyclic or tricyclic fused ring group include the groups shown in the following Class (4):
Class (4):
a hydroxyl group,
an alkyl group,
an alkenyl group,
a halogenoalkyl group,
a halogenoalkenyl group,
an alkoxyl group,
a hydroxyalkyl group,
an alkoxyalkyl group,
a halogen atom,
a cyano group,
a nitro group,
a carboxyl group,
an alkoxycarbonyl group,
a formyl group,
a heteroaryl group,
a heteroarylalkyl group,
an alkylimino group,
an amidino group,
a guanidino group,
an amino(hydroxyimino)alkyl group,
an amino(alkoxyimino)alkyl group,
an amino(aryloxyimino)alkyl group,
an amino group which may have one or two substituents,
an aminocarbonyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyl group in which the amino moiety may have one or two substituents,
an aminocarbonylalkyloxy group in which the amino moiety may have one or two substituents,
an aminoalkyl group in which the amino moiety may have one or two substituents,
an aminoalkyloxy group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyl group in which the amino moiety may have one or two substituents,
an aminoalkylcarbonyloxy group in which the amino moiety may have one or two substituents,
an oxygen atom,
a trifluoromethylsulfonyloxy group,
a trifluoromethylsulfonyloxyalkenyl group,
a boric acid group (xe2x80x94B(OH2)),
a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, alkoxyl, alkyl, cyano, nitro, carboxyl, alkoxycarbonyl and aminocarbonyl, and
a saturated or unsaturated 5- or 6-membered heterocyclic group which may have 1 to 3 substituents selected from the group consisting of halogen, hydroxyl, amino, alkoxyl, alkyl, cyano, nitro, carboxyl, alkoxycarbonyl and aminocarbonyl.
Incidentally, the number of the replaceable substituents ranges from 1 to 7. The substituents in Class (4) have the same meanings as described in Classes (1) to (3).
In the present invention, preferred examples of Q1 include a phenyl group which may have a substituent, an imidazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyrrolidinyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent and a tetrahydrothiazolopyridyl group which may have a substituent.
In Q2, examples of the linear or branched C1-6 alkylene group include methylene, ethylene, trimethylene, propylene, tetramethylene, butylene, pentamethylene and hexamethylene.
Examples of the linear or branched C2-6 alkenylene group include vinylene, propenylene, butenylene and pentenylene. There is no particular limitation on the position of the double bond.
Examples of the linear or branched C2-6 alkynylene group include propynylene, butynylene, pentynylene and hexynylene.
The following group: 
means a divalent, saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a divalent, saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, or a divalent, saturated or unsaturated dicyclic fused group which may have a substituent, and ←C means the bonding of the carbon atom of this group to Q1. Examples of this group include divalent groups derived from thiophene, furan, pyran, pyrrole, pyrrolidine, pyrroline, imidazole, imidazoline, imidazolidine, pyrazole, pyrazolidine, thiazole, oxazole, oxathiolan, benzene, pyridine, piperidine, piperazine, morpholine, thiomorpholine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, thiadiazine, dithiazine, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, cyclohexadiene or the like and they may have a substituent. As the substituent, those exemplified above in Class (4) can be mentioned as examples.
The alkyl group in R6 or R7 of the group xe2x80x94N(R6)xe2x80x94COxe2x80x94 or xe2x80x94N(R7)xe2x80x94(CH2)mxe2x80x94 means a linear, branched or cyclic C1-6 alkyl group. Examples include methyl, ethyl, isopropyl and cyclopropyl. As the group xe2x80x94N(R6)xe2x80x94COxe2x80x94, a group ←N(R6)xe2x80x94COxe2x80x94 (wherein ← means the bonding of the nitrogen atom of this group to Q1) is preferred, while as the group xe2x80x94N(R7)xe2x80x94(CH2)mxe2x80x94, a group ←N(R7)xe2x80x94(CH2)mxe2x80x94 (wherein ← means the bonding of the nitrogen atom of this group to Q1) is preferred.
In the present invention, preferred examples of Q2 include a single bond, a carbonyl group and groups represented by the following formula: 
Among the groups represented by the following formula: 
divalent groups derived from benzene, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazine, tetrazine, imidazole, imidazoline, thiazole, thiazoline, furan, thiophene, pyrrole, oxazole, oxazoline, thiadiazole, cyclopentane, cyclopentene, cyclohexane or cyclohexene are preferred.
In R8, R9, R10, R11, R12, R13, R15 and R16 as the substituents in Q3, the alkyl, alkoxyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkyloxy, hydroxyalkylcarbonyl, hydroxyalkylsulfonyl, formylalkyl, formylalkylcarbonyl, formylalkylsulfonyl, alkylcarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkylcarbonyl, carboxyalkylsulfonyl, carboxyalkylcarbonylalkyl, carboxyalkylsulfonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkylsulfonyl, amino which may have 1 to 2 substituents, aminoalkyl in which the amino moiety may have 1 or 2 substituents, aminoalkylcarbonyl in which the amino moiety may have 1 or 2 substituents, aminoalkylcarbonyloxy in which the amino moiety may have 1 or 2 substituents, aminocarbonyl in which the amino moiety may have 1 or 2 substituents, aminocarbonylalkyl in which the amino moiety may have 1 or 2 substituents, and aminocarbonylalkyloxy in which the amino moiety may have 1 or 2 substituents have the same meanings as described above in R1.
The xe2x80x9calkoxyalkyloxy groupxe2x80x9d means a group formed of the above-described alkoxyalkyl group and an oxygen atom and examples include methoxymethyloxy, methoxyethyloxy and ethoxymethyloxy.
The xe2x80x9ccarboxyalkyl groupxe2x80x9d means a group formed of a carboxyl group and the above-described C1-6 alkylene group and examples include carboxymethyl and carboxyethyl.
The xe2x80x9ccarboxyalkyloxy groupxe2x80x9d means a group formed of the above-described carboxylalkyl group and an oxygen atom and examples include carboxymethoxyl and carboxyethoxyl.
The xe2x80x9calkoxycarbonylalkyloxy groupxe2x80x9d means a group formed of the above-described alkoxycarbonylalkyl group and an oxygen atom and examples include methoxycarbonylethyl and ethoxycarbonylethyl.
The xe2x80x9caminoalkyloxy group in which the amino moiety may have 1 or 2 substituentsxe2x80x9d means a group formed of an amino group which may have a substituent, a linear, branched or cyclic C2-6 alkylene group and an oxygen atom and examples include aminoethoxyl and aminopropoxyl.
In the group A2-B2xe2x80x94, A2 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent. Here, examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has various structural isomers as the cyclopentenyl, they are all embraced in it.
The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group having at least one hetero atom. Examples of the hetero atom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. Where the group has plural structural isomers as the pyranyl, it is to be noted that they are all embraced in it.
B2 represents a single bond, carbonyl group or alkylene group. The xe2x80x9calkylene groupxe2x80x9d means a linear, branched or cyclic C1-6 alkylene group.
Examples of the group A2-B2xe2x80x94 include the following groups:
a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent,
a group formed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and a carbonyl group, and
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and an alkylene group.
Each of R8 and R9, R10 and R11, R12 and R13, and R15 and R16 is coupled together with a carbon atom which constitutes the ring and represents a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent. Here, examples of the saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has various structural isomers as the cyclopentenyl, they are all embraced in it.
The saturated or unsaturated 5- to 7-membered heterocyclic group is a cyclic group having at least one hetero atom. Examples of the hetero atom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- to 7-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. Where the group has plural structural isomers as the pyranyl, it is to be noted that they are all embraced in it.
a, b, d, e and g each independently stands for an integer of 0 or 1, c stands for an integer of 0 to 3 and f, h and i each independently represents an integer of 1 to 3, with the proviso that the sum of a, b and c stands for an integer of 2 or 3, the sum of d and e stands for an integer of 0 or 1 and the sum of f, g and h stands for an integer of 3 to 5.
In R14 or R17 as the substituent in Q3, the alkyl, alkoxyl, hydroxyalkylcarbonyl, hydroxyalkylsulfonyl, alkoxyalkylcarbonyl, alkoxyalkylsulfonyl, formylalkyl, formylalkylcarbonyl, formylalkylsulfonyl, alkylcarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkylcarbonyl, carboxyalkylsulfonyl, carboxyalkylcarbonylalkyl, carboxyalkylsulfonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkylsulfonyl, amino which may have 1 to 2 substituents, aminoalkylcarbonyl in which the amino moiety may have 1 or 2 substituents, aminoalkyloxycarbonyl in which the amino moiety may have 1 or 2 substituents, aminocarbonyl in which the amino moiety may have 1 or 2 substituents, aminocarbonylalkyl in which the amino moiety may have 1 or 2 substituents, and aminocarbonyloxyalkyl in which the amino moiety may have 1 or 2 substituents have the same meanings as described above in R1.
The xe2x80x9chydroxyalkyl groupxe2x80x9d means a group formed of a hydroxyl group and a linear, branched or cyclic C2-6 alkylene group and examples include hydroxyethyl and hydroxypropyl.
The xe2x80x9calkoxyalkyl groupxe2x80x9d means a group formed of the above-described alkoxyl group and a linear, branched or cyclic C2-6 alkylene group and examples include methoxyethyl and ethoxyethyl. The xe2x80x9caminoalkyl group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described amino group which may have a substituent and a linear, branched or cyclic C2-6 alkylene group and examples include aminoethyl and aminopropyl.
The xe2x80x9caminoalkyloxy group in which the amino moiety may have one or two substituentsxe2x80x9d means a group formed of the above-described amino group which may have a substituent, a linear, branched or cyclic C2-6 alkylene group and an oxygen atom and examples include aminoethoxyl and aminopropoxyl.
In the group A3-B3xe2x80x94, A3 represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent. Here, examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. When the group has various structural isomers as the cyclopentenyl, they are all embraced in it.
The saturated or unsaturated S- or 6-membered heterocyclic group is a cyclic group having at least one hetero atom. Examples of the hetero atom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. Where the group has plural structural isomers as the pyranyl, it is to be noted that they are all embraced in it.
B3 represents a single bond, carbonyl group or alkylene group. The xe2x80x9calkylene groupxe2x80x9d means a linear, branched or cyclic C1-6 alkylene group.
Examples of the group A3-B3xe2x80x94 include the following groups: a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent,
a group formed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and a carbonyl group, and
a group formed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and an alkylene group.
R14 and R12, R14 and R13, R17 and R15, and R17 and R16 are each coupled together with the carbon atom which constitutes the ring and the nitrogen atom to which R14 or R17 has been bonded and represent a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent. Here, examples of the saturated or unsaturated 5- to 7-membered heterocyclic group is a cyclic group which has at least one nitrogen atom and may have a hetero atom. Examples of the hetero atom include oxygen, nitrogen and sulfur. Examples of the saturated or unsaturated 5- to 7-membered heterocyclic group include furyl, pyrrolyl, thienyl, pyrazolyl, pyrazinyl, tetrahydropyrazinyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, thiazolidinyl, oxatriazolyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyridazinyl, tetrahydropyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, tetrazinyl, triazolyl and triazinyl. Where the group has plural structural isomers as the pyranyl, it is to be noted that they are all embraced in it.
In the present invention, Q3 represents a group of the following formula: 
(wherein R8, R9, R10, R12, R13, R14, R15, R16, R17, a, b, c, d, e, f, g, h and i have the same meanings as described above), with the group of the following formula: 
(wherein R8, R9, a, b and c have the same meanings as described above) being preferred.
T1 represents a carbonyl group,
a group xe2x80x94CH(R18)xe2x80x94
(in which R18 represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group in which the amino moiety may have a substituent) or
a group xe2x80x94C(xe2x95x90NOR19 )xe2x80x94
(in which R19 represents a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an aminoalkyl group in which the amino moiety may have a substituent).
Here, the alkyl, carboxyalkyl, alkoxycarbonyl, aryl, aralkyl, heteroaryl, heteroarylalkyl and aminoalkyl in which the amino moiety may have a substituent in R18 or R19 have the same meanings as described in R1. In the present invention, a carbonyl group is preferred as T1.
In the present invention, the group: 
in the formula (1) means a group: 
or another group: 
and,
R4 represents a halogen atom.
In the present invention, preferred as Q1 are a cyclopentyl group which may have a substituent, a cyclohexyl group which may have a substituent, a cyclopentenyl group which may have a substituent, a cyclohexenyl group which may have a substituent, a phenyl group which may have a substituent, a pyrrolidinyl group which may have a substituent, a piperidinyl group which may have a substituent, an imidazolyl group which may have a substituent, a thiazolyl group which may have a substituent, a thiadiazolyl group which may have a substituent, a pyridyl group which may have a substituent, a pyrimidinyl group which may have a substituent, a pyridazinyl group which may have a substituent, a thiazolidinyl group which may have a substituent, a morpholinyl group which may have a substituent, a piperazinyl group which may have a substituent, a thiomorpholinyl group which may have a substituent, a pyrrolyl group which may have a substituent, a thienyl group which may have a substituent, a furanyl group which may have a substituent, a tetrahydropyrimidinyl group which may have a substituent, a tetrahydrofuranyl group which may have a substituent, a tetrahydrothienyl group which may have a substituent, a sulfolanyl group which may have a substituent, an imidazolinyl group which may have a substituent, a thiazolinyl group which may have a substituent, an oxazolyl group which may have a substituent, an oxadiazinyl group which may have a substituent, a triazinyl group which may have a substituent, a tetrazinyl group which may have a substituent, a pyrazinyl group which may have a substituent, a pyrazolyl group which may have a substituent, a pyrazolinyl group which may have a substituent, a pyrazolidinyl group which may have a substituent, a thienopyridyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent, a thiazolopyridyl group which may have a substituent, and a tetrahydrothiazolopyridyl group which may have a substituent.
Preferred as the substituent are saturated or unsaturated, 5- or 6-membered cyclic hydrocarbon groups each of which may have 1 to 3 substituents selected from the group consisting of a hydroxyl group, alkyl groups, hydroxyalkyl groups, halogen atoms, a cyano group, a nitro group, a carboxyl group, alkoxycarbonyl groups, a formyl group, alkylsulfonyl groups, amino groups which may have 1 or 2 substituents, aminosulfonyl groups which may have, at the amino moiety thereof, 1 or 2 substituents, aminoalkyl groups which may have, at the amino moiety thereof, 1 or 2 substituents, an oxygen atom, a trifluoromethyl group, halogen atoms, a hydroxyl group, amino groups, alkoxyl groups, alkyl groups, a cyano group, a nitro group, a carboxyl group, alkoxycarbonyl groups, aminocarbonyl groups which may have, at the amino moiety thereof, 1 or 2 substituents, aminosulfonyl groups which may have, at the amino moiety thereof, 1 or 2 substituents, aminoalkyl groups which may have, at the amino moiety thereof, 1 or 2 substituents and a trifluoromethyl group; and saturated or unsaturated 5- or 6-membered heterocyclic groups each of which may have 1 to 3 substituents selected from the group consisting of halogen atoms, a hydroxyl group, amino groups, alkoxyl groups, alkyl groups, a cyano group, a nitro group, a carboxyl group, alkoxycarbonyl groups, aminocarbonyl groups which may have, at the amino moiety thereof, 1 or 2 substituents, aminosulfonyl groups which may have, at the amino moiety thereof, 1 or 2 substituents, aminoalkyl groups which may have, at the amino moiety thereof, 1 or 2 substituents and a trifluoromethyl group.
In the present invention, preferred examples of Q2 include a single bond, a carbonyl group and groups represented by the following formula: 
Among the groups represented by the following formula: 
divalent groups derived from benzene, pyrimidine, tetrahydropyrimidine, pyrazine, pyridazine, triazine, tetrazine, imidazole, imidazoline, thiazole, thiazoline, furan, thiophene, pyrrole, oxazole, oxazoline, thiadiazole, cyclopentane, cyclopentene, cyclohexane or cyclohexene are preferred.
Particularly preferred is the case where: Q3 means the following group: 
[wherein, R8, R9, a, b and c have the same meanings as described above]; and
T1 represents a carbonyl group.
The sulfonyl derivative of the present invention has optical isomers or stereoisomers based on an asymmetric carbon atom. These optical isomers and stereoisomers and mixtures thereof are all embraced in the present invention.
There is no particular limitation imposed on the salt of the sulfonyl derivative according to the present invention insofar as it is pharmaceutically acceptable. Specific examples include salts of a mineral acid such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate and sulfate, benzoate, salts of an organic sulfonic acid such as methanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate and salts of an organic carboxylic acid such as acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and mandelate. There is no particular limitation imposed on the solvate insofar as it is pharmaceutically acceptable. Specific examples include hydrates and ethanolates.
The following are the preferred compounds as the sulfonyl derivative of the present invention.
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine-2-carboxylic acid hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)nicotinyl]piperazine hydrochloride
4-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
1-[4-(2-Aminopyridin-5-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-[imidazol-4(5)-yl]benzoyl]piperazine hydrochloride
1-[4-[2-Aminoimidazol-4-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
2-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
2-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-1-methylpyridinium iodide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2,4-diaminopyrimidin-6-yl)benzoyl]piperazine hydrochloride
1-[(E)-4-Chlorostyrylsulfonyl]-4-[4-(2,4-diaminopyrimidin-6-yl)benzoyl]piperazine hydrochloride
2-[4-[[4-[(E)-4-Chlorostyrylsulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
1-[(E)-4-Chlorostyrylsulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
3-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]-1-methylpyridinium iodide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[2-hydroxy-4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-4-[4-(pyridin-4-yl)benzoyl]piperazine
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine-2-carboxylic acid
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-3-yl)benzoyl]piperazine hydrochloride
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
4-[4-[[2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[4-[[2-Carboxy-4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
2-Carbamoyl-4-[(E)-4-chlorostyrylsulfonyl]-[1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
1-[trans-4-(Aminomethyl)cyclohexylcarbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
1-[[(6RS)-6-Aminomethyl-5,6,7,8-tetrahydronaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
1-[(7-Aminomethylnaphthalen-2-yl]carbonyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[4-[[(3S)-pyrrolidin-3-yl]oxy]benzoyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl]sulfonyl]-4-[4-[(3RS)-pyrrolidin-3-yl)benzoyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonyl-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
2-Carboxy-4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(5-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[5-(1-pyrrolin-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl]carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-formyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6,6-dimethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinium iodide
2-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine N-oxide
2-Carbamoyl-4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine trifluoroacetate
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(2-hydroxyethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[6-(pyridin-3-yl)methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]piperazine hydrochloride
1-[(E)-4-Chlorostyrylsulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[(1RS)-4-(pyridin-4-yl)-3-cyclohexenyl]carbonyl]piperazine hydrochloride
cis-, trans-1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[[4-(pyridin-4-yl)cyclohexanyl]carbonyl]piperazine hydrochloride
6-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(1,2,3,6-tetrahydropyridin-4-yl)benzoyl]piperazine hydrochloride
1-[[(E)-2-(6-Chloropyridin-3-yl)vinyl]sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[2-methyl-4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
4-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-2-methylphenyl]pyridine N-oxide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-methylpyridin-4-yl)benzoyl]piperazine hydrochloride
4-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-piperazin-1-yl]carbonyl]phenyl]-2-methylpyridine N-oxide
4-[4-[[4-(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[2-(morpholin-4-yl)ethylamino]carbonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-[[2-(dimethylamino)ethylamino]carbonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-methoxycarbonylmethyl-1-[4-(pyridin-2-yl)benzoyl]piperazine
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-carboxymethyl-1-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
2-Carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
1-[4-[(3RS)-1-Acetimidoylpyrrolidin-3-yl]benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-acetoxymethylpyrrolidin-4-yl)benzoyl]piperazine
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(2-hydroxymethylpyridin-4-yl)benzoyl]piperazine hydrochloride
2-Hydroxymethyl-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl)carbonyl]phenyl]pyridine N-oxide
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(2-aminoimidazol-4-yl)benzoyl]piperazine
2-[[1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-4-yl]carbonyl-4-phenyl]-6-methylpyridine N-oxide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(6-methylpyridin-2-yl)benzoyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(3-aminopyridin-2-yl)benzoyl]piperazine hydrochloride
4-[4-[[1-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-4-yl]carbonyl]-3-methylphenyl]pyridine N-oxide
1-[2-tert-Butoxycarbonyl-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine
1-[2-Carboxy-4-(pyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine
1-(4-Amidinobenzoyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-[imidazol-4(5)-yl]benzoyl]piperazine hydrochloride
1-[4-(2-Aminopyridin-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride
1-[4-(2-Aminothiazol-4-yl)benzoyl]-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine
2-Carbamoyl-4-[(E)-4-chlorostyrylsulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
4-[5-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]pyridin-2-yl]pyridine N-oxide
2-Amino-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[4-[[4-[(E)-4-Chlorostyrylsulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-ethoxycarbonylpiperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-methoxycarbonylmethyl-1-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
2-Carboxymethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
2-Carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
2-[4-[[2-carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
2-Methyl-4-[4-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,3-dimethyl-4-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
2-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-hydroxymethyl-3-methylpiperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,3-dimethylpiperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,6-dimethyl-1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,2-dimethyl-1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
2-[4-[[4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,2-dimethylpiperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-oxo-1-[4-(pyridin-4-yl)benzoyl]piperazine N-oxide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-2,3-dicarbamoyl-4-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-methyl-3-[2-(morpholin-4-yl)ethylamino]carbonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
4-[4-[[4-(6-Chloronaphthalen-2-yl)sulfonyl-3-methyl-2-[[2-(morpholin-4-yl)ethylamino]carbonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
2-Carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-3-methyl-1-[4-(pyridin-4-yl)benzoyl]piperazine hydrochloride
4-[4-[[2-Carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-6-methylpiperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
2-[4-[[2-Carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-6-oxopiperazin-1-yl]carbonyl]phenyl]pyridine N-oxide
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-2-yl)benzoyl]-1,2,3,4-tetrahydroquinoxaline hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]decahydroquinoxaline hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-[(ethoxycarbonylmethylsulfonylamino)methyl]-2-methyl-4-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
2-Carbamoylmethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-3-oxo-1-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-3-(imidazol-4-yl)methyl-2-oxo-4-[4-(pyridin-2-yl)benzoyl]piperazine hydrochloride
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]-7-oxodecahydropyrido[3,4-b]pyrazine hydrochloride.
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-3-methyl-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-6-methyl-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride
4-[(6-Chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[2-(morpholin-4-yl)ethylamino]carbonyl]piperazine hydrochloride
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)carbonyl]piperazine hydrochloride
2-Carbamoyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]-3-methyl-1-[(6-methyl-5,6,7,8-tetrahydropyrido-1,6-naphthyridin-2-yl)carbonyl]piperazine hydrochloride
The process for the preparation of the sulfonyl derivative of the present invention will next be described.
The sulfonyl derivative, salt thereof and solvate thereof according to the present invention can be prepared by using general, conventionally-known chemical processes in combination. Typical synthesis processes will be described subsequently.
Upon synthesis of the sulfonyl derivative of the present invention, when it is necessary to protect a substituent such as nitrogen atom, hydroxyl group or carboxyl group, it may be protected with a ordinary, conventionally-known protecting group which can be removed as needed. Such a protecting group can be removed at need by the synthesis process ordinarily employed in the organic chemistry which will be described below. The starting materials necessary for the synthesis can be obtained by the synthesis process ordinarily employed in the organic chemistry and such a process will be described in Referential Examples. The starting materials can also be synthesized by the application of the process described in Referential Examples.
A description will next be made of a protecting group for the substituent such as nitrogen atom, hydroxyl group or carboxyl group and deprotection process thereof.
As a protecting group for the nitrogen atom in an amino or alkylamino group, ordinary acyl-type protecting groups are suited. Examples include alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and tertiary butoxy carbonyl, arylmethoxycarbonyl groups such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl and para-(ortho-)nitrobenzyloxycarbonyl groups, aryolmethyl groups such as benzyl and triphenylmethyl and aroyl groups such as benzoyl. The removing process of such a protecting group differs with the chemical properties of the protecting group adopted. For example, the acyl-type protecting group such as alkanoyl, alkoxycarbonyl or aroyl can be removed by hydrolysis using an appropriate base such as alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide.
The substituted methoxycarbonyl type protecting group such as tertiary butoxycarbonyl or paramethoxybenzyloxycarbonyl can be removed by using an appropriate acid, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid or combination thereof. The arylmethoxycarbonyl group such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl or para-(ortho-)nitrobenzyloxycarbonyl, or the arylmethyl group such as benzyl can be removed by hydrogenolysis in the presence of a palladium-carbon catalyst. The benzyl group can also be removed by Birch reduction, in liquid ammonia, in the presence of a metal sodium, whereby conversion into a nitrogen-hydrogen bond can be effected. The triphenylmethyl group can be removed by using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid or combination thereof. It can also be removed by Birch reduction, in liquid ammonia, in the presence of a metal sodium or by hydrogenolysis in the presence of a palladium-carbon catalyst.
In addition to the above-described amino-protecting group, a phthaloyl type protecting group can be adopted for a primary amino group and it can be removed using hydrazine, dimethylaminopropylamine or the like.
As the protecting group suited for a hydroxyl group, there are acyl type and ether type ones. Examples of the acyl type protecting group include alkanoyl groups such as acetyl and aroyl groups such as benzoyl, while those of the ether type protecting group include arylmethyl groups such as benzyl, silyl ether groups such as tertiary butyl dimethylsilyl, methoxymethyl and tetrahydropyranyl. The removal of such a protecting group differs with the chemical properties of the protecting group adopted. For example, the acyl group such as alkanoyl or aroyl can be removed by the hydrolysis using an appropriate base such as an alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide. The arylmethyl type protecting group can be removed by the hydrogenolysis using a palladium-carbon catalyst. The silyl group such as tertiary butyl dimethylsilyl can be removed using a hydrofluoride salt such as tetrabutyl ammonium fluoride. The methoxymethyl or tetrahydropyranyl group can be removed using acetic acid, hydrochloric acid or the like. The hydroxyl group substituted for an aryl group can be protected with a methyl group and deprotection can be carried out using a Lewis acid such as aluminum chloride or phosphorus tribromide, trimethylsilyl iodide or hydrogen bromide.
A carboxyl group can be protected by the esterification of it. A methyl or ethyl ester can be deprotected by the hydrolysis using an appropriate base such as alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide or potassium hydroxide, while from a tertiary butyl ester, the tertiary butyl group can be removed by treating with trifluoroacetic acid or hydrochloric acid. From an arylmethyl type ester such as benzyl, the arylmethyl group can be removed by the hydrogenolysis in the presence of a palladium-carbon catalyst.
[Preparation Process-1]
A process for preparing a sulfonyl derivative represented by the following formula (I): 
[wherein R1, R2, R3, R4, R5, Q1, Q2, Q3, T1, X1 and X2 have the same meanings as described above], which comprises sulfonylating the nitrogen atom of Q3a of the compound represented by the following formula (Ia):
Q1xe2x80x94Q2xe2x80x94T1xe2x80x94Q3axe2x80x83xe2x80x83(Ia)
[wherein Q1, Q2 and T1 have the same meanings as described above and Q3a represents any one of the groups represented by the following formulas: 
(in which R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, a, b, c, d, e, f, g, h and i have the same meanings as described above)] with a sulfonic acid halide represented by the following formula (IIa): 
[wherein R1, R2, R3, R4, R5, X1 and X2 have the same meanings as described above and Halo represents a halogen atom such as chlorine, bromine or iodine].
 less than Synthesis of the Compound of the Formula (Ia) greater than 
The compound of the formula (Ia) can be synthesized by a series of operations in accordance with the known technique.
For example, a compound of the following formula (Ib):
Q1xe2x80x94Q2xe2x80x94T1xe2x80x94Q3bxe2x80x83xe2x80x83(Ib)
[wherein Q1, Q2 and T1 have the same meanings as described above and Q3b represents any one of the following groups: 
(in which R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, a, b, c, d, e, f, g, h and i have the same meanings as described above and R21 represents an ordinary nitrogen protecting group such as tertiary butoxycarbonyl, benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl or benzyl)] can be synthesized by acylating the nitrogen atom of the compound represented by the following formula (IIIa):
Q3bxe2x80x94Hxe2x80x83xe2x80x83(IIIa)
(wherein Q3 has the same meaning as described above), to which nitrogen atom, the hydrogen atom of Q3b has been bonded, with a carboxylic acid in an activated form represented by any one of the following formulas (IVa) to (IVd):
Q1xe2x80x94Q 2bxe2x80x94COOHxe2x80x83xe2x80x83(IVa)
Q1xe2x80x94N(R20)xe2x80x94(CH2)m1xe2x80x94COOHxe2x80x83xe2x80x83(IVb)
Q1xe2x80x94Oxe2x80x94(CH2)m1xe2x80x94COOHxe2x80x83xe2x80x83(Ivc)
Q1xe2x80x94Sxe2x80x94(CH2)m1xe2x80x94COOHxe2x80x83xe2x80x83(Ivd)
[wherein Q1 has the same meaning as described above, R20 represents a linear or branched alkylene or an ordinary nitrogen protecting group such as tertiary butoxycarbonyl, benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl or benzyl, Q2b represents single bond, a linear or branched C1-6 alkylene, linear or branched C2-6 alkenylene, linear or branched C2-6 alkynylene or a group of the following formula: 
(which has the same meaning as described above) and m1 stands for an integer of 1 to 6].
When the nitrogen atom of Q3b of the compound represented by the formula (IIIa) forms an amide bond, the compound of the formula (Ib) can be synthesized by alkylating the nitrogen atom of Q3b of the compound represented by the formula (IIIa) with any one of the compounds represented by the following formulas (Va) to (Vd):
Q1xe2x80x94Q2bxe2x80x94CHL1R18xe2x80x83xe2x80x83(Va)
Q1xe2x80x94N(R20)xe2x80x94(CH2)m1xe2x80x94CHL1R18xe2x80x83xe2x80x83(Vb)
Q1xe2x80x94Oxe2x80x94(CH2)m1xe2x80x94CHL1R18xe2x80x83xe2x80x83(Vc)
Q1Sxe2x80x94(CH2)m1xe2x80x94CHL1R18xe2x80x83xe2x80x83(Vd)
[wherein Q1, Q2b, R18, R20 and m1 have the same meanings as described above, and L1 represents an eliminating group frequently used in the organic chemistry, such as chlorine, bromine, iodine, methylsulfonyloxy or paratoluenesulfonyloxy].
When the nitrogen atom of Q3b of the compound represented by the formula (IIIa) exists as a primary or secondary amine, the compound of the formula (Ib) can be prepared by reductive alkylation, that is, by forming the corresponding imine with a carbonyl compound represented by any one of the following formulas (VIa) to (VId):
Q1xe2x80x94Q2bxe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VIa)
Q1xe2x80x94N(R20)xe2x80x94(CH2)m1xe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VIb)
Q1xe2x80x94Oxe2x80x94(CH2)m1xe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VIc)
Q1Sxe2x80x94(CH2)m1xe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VId)
[wherein Q1, Q2b, R18, R20 and m1 have the same meanings as described above], followed by reduction; by reacting the compound of the formula (IIIa) with a reagent such as 1,1xe2x80x2-carbonyldiimidazole and a compound containing a primary amine represented by any one of the following formulas (VIIa) to (VIId):
Q1xe2x80x94Q2xe2x80x94NH2xe2x80x83xe2x80x83(VIIa)
Q1xe2x80x94N(R20)xe2x80x94(CH2)m2xe2x80x94NH2xe2x80x83xe2x80x83(VIIb)
A1xe2x80x94Oxe2x80x94(CH2)m2xe2x80x94NH2xe2x80x83xe2x80x83(VIIc)
Q1xe2x80x94Sxe2x80x94(CH2)m2xe2x80x94NH2xe2x80x83xe2x80x83(VIId)

[wherein Q1, Q2 and R20 have the same meanings as described above and m2 stands for an integer of 2 to 6 and a group of the following formula: 
represents a 5- or 6-membered heterocyclic group which may have a substituent], thereby forming an urea derivative; or by reacting the amine of the formula (IIIa) with an isocyanate derivative or an isocyanate prepared from a carboxylic acid represented by any one of the formulas (IVa) to (IVd).
When in the structure of Q1 of the compound represented by the formula (Ib), a halogen- or trifluoromethanesulfonyloxy-substituted aryl group or a halogen- or trifluoromethanesulfonyloxy-substituted alkenyl group is contained, coupling reaction can be effected with a boric-acid-substituted aryl compound in the presence of a transition metal catalyst.
When in the structure of Q1 of the compound represented by the formula (Ib), an alkenyl group is contained, it can be subjected to coupling reaction with a halogen-substituted or trifluoromethanesulfonyloxy-substituted aryl group in the presence of a transition metal catalyst.
When in the structure of Q1 of the compound represented by the formula (Ib), a boric-acid-substituted aryl group is contained, it can be subjected to coupling reaction with a halogen- or trifluoromethanesulfonyloxy-substituted aryl compound or a halogen- or trifluoromethanesulfonyloxy-substituted alkenyl compound. When in the structure of Q1 of the compound represented by the formula (Ib), a halogen- or trifluoromethanesulfonyloxy-substituted aryl group is contained, it can be subjected to coupling reaction with an alkenyl compound in the presence of a transition metal catalyst. If the nitrogen atom of Q3b of the compound (Ib) so obtained has been protected, the compound of the formula (Ia) can be obtained by deprotection as needed.
Examples of the carboxylic acids of the following formulas (IVa) to (IVd) in an activated form include mixed acid anhydrides available by reacting any one of the carboxylic acids of the formulas (IVa) to (IVd) with a chloroformate ester such as isobutyl chloroformate, acid halides such as acyl chloride prepared using an acid halide such thionyl chloride, active esters obtained by reacting with a phenol such as paranitrophenol or pentafluorophenyl-trifluoroacetate, active esters obtained by reacting with N-hydroxybenztriazole or N-hydroxysuccinimide, reaction products with N,Nxe2x80x2-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride which is usually employed for the synthesis of amino acid peptide, reaction products with diethyl cyanophosphonate (Shioiri""s method) and reaction products with triphenylphosphine and 2,2xe2x80x2-dipyridylsulfide (Mukaiyama""s method).
The resulting carboxylic acid in an activated form is then reacted with the compound of the formula (IIIa) or salt thereof generally in the presence of an appropriate base in an inert solvent at xe2x88x9278xc2x0 C. to 150xc2x0 C., whereby the compound of the formula (Ib) can be obtained. Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium botoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
Examples of the inert solvent include alkyl halide solvents such as dichloromethane, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic solvents such as benzene and toluene; and amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one. In addition to them, sulfoxide solvents such as dimethylsulfoxide and sulfolane and ketone solvents such as acetone and methyl ethyl ketone can be used if they are suited.
When the nitrogen atom of Q3b of the compound represented by the formula (IIIa) forms an amide bond, the alkylation of the nitrogen atom is carried out by reacting the compound (IIIa) with the compound represented by any one of the formulas (Va) to (Vd) in the presence of an appropriate base in an inert solvent at xe2x88x9278 to 150xc2x0 C., whereby the compound of the formula (Ib) can be obtained. Specific examples of the base include alkoxides and hydrides of an alkali metal or alkaline earth metal such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride; organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide; and organic bases such as diazabicyclo[5.4.0]undec-7-ene (DBU).
Examples of the inert solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane and amide solvents such as N,N-dimethylformamide.
When the nitrogen atom of Q3b of the compound represented by the formula (IIIa) exists as a primary or secondary amine, the compound of the formula (Ib) can be obtained by reacting the compound of the formula (IIIa) with the carbonyl compound of any one of the formulas (VIa) to (VId), to form the corresponding imine, generally in an inert solvent, in the presence of an organic acid such as acetic acid, a mineral acid such as hydrochloric acid or a Lewis acid such as aluminum chloride at xe2x88x9220 to 150xc2x0 C.; and then hydrogenating the resulting imine in an inert solvent in the presence of a boron hydride reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride or a catalytic reduction catalyst such as palladium-carbon catalyst at 10 to 110xc2x0 C.
Preferred examples of the inert solvent include carbon halides such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, benzene solvents such as toluene and amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one.
When the nitrogen atom of Q3 of the compound represented by the formula (IIIa) exists as a primary or secondary amine, the reaction product between the compound of any one of the formulas (VIIa) to (VIIb) containing a primary amine or the compound of the formula (VIle) containing a secondary amine and a reagent such as 1,1xe2x80x2-carbonyldiimidazole can be reacted with the compound of the formula (IIIa) to introduce it to the corresponding urea derivative. The derivative can be synthesized by reacting the primary amine compound of any one of the formulas (VIIa) to (VIId) or the secondary amine compound of the formula (VIIe), a reagent such as carbonyldiimidazole and the compound of the formula (IIIa) successively in this order, if necessary in the presence of a base, in an inert solvent.
Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; benzene solvents such as toluene; and amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one. Among them, dichloromethane, tetrahydrofuran and toluene are preferred.
Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is effected within a temperature range of from -xe2x88x9270xc2x0 C. to 110xc2x0 C.
When the nitrogen atom of Q3b of the compound represented by the formula (IIIa) exists as a primary or secondary amine, the compound of the formula (Ib) can also be obtained by reacting the compound of the formula (IIIa) with an isocyanate derivative in an inert solvent at xe2x88x9220 to 100xc2x0 C.
The isocyanate derivative can be synthesized by converting the carboxylic acid of the formula (IVa) into the corresponding acid halide by using an acid halide such as thionyl chloride or oxalyl chloride in an inert solvent such as tetrahydrofuran, chloroform or toluene at xe2x88x9220 to 110xc2x0 C., reacting the resulting acid halide with sodium azide in an inert solvent such as tetrahydrofuran, chloroform or toluene at a temperature range of from 0 to 80xc2x0 C., and then heating the reaction mixture at 20 to 100xc2x0 C.; reacting the carboxylic acid of the formula (IVa) with a chloroformate such as isobutyl chloroformate in an inert solvent such as tetrahydrofuran, chloroform or toluene at xe2x88x9220 to 110xc2x0 C. to obtain the corresponding mixed acid anhydride, reacting the mixed acid anhydride with sodium azide within a temperature range of from 0 to 80xc2x0 C. and then heating the reaction mixture at 20 to 100xc2x0 C.; or by introducing the carboxylic acid of the formula (IVa) into the corresponding hydrazide through an ester in an inert solvent such as tetrahydrofuran, chloroform or toluene at xe2x88x9220 to 110xc2x0 C., reacting the hydrazide with nitric acid or alkyl ester thereof to convert it into the corresponding acyl azide and then heating the resulting acyl azide in a solvent such as chloroform, dichloroethane, toluene, xylene or N,N-dimethylformamide at 20 to 150xc2x0 C.
The compound of the formula (Ib) can also be prepared by reacting the carboxylic acid of the formula (IVa) with diphenylphosphoryl azide in the presence of a base such as triethylamine, in an inert solvent such as chloroform, tetrahydrofuran, toluene or N,N-dimethylformamide at a temperature range of 10 to 140xc2x0 C. and then reacting the reaction mixture with the amine of the formula (IIIa).
When in the structure of Q1 of the compound represented by the formula (Ib), a halogen- or trifluoromethanesulfonyloxy-substituted aryl group or a halogen- or tri-fluoromethanesulfonyoxy-substituted alkenyl group is contained, the compound can be subjected to coupling reaction with a boric-acid-substituted aryl derivative by using a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (O), in a two-phase solvent such as benzene-water or toluene-water, amide solvent such as N,N-dimethylformamide or ether solvent such as tetrahydrofuran or dimethoxyethane, in the presence of a base such as sodium carbonate, sodium hydroxide, barium hydroxide, potassium phosphate or cesium carbonate at a temperature range of 20 to 150xc2x0 C. for 0.5 to 120 hours.
When an alkenyl group is contained in the structure of Q1 of the compound represented by the formula (Ib), coupling reaction of the compound with a halogen- or trifluoromethanesulfonyloxy-substituted aryl group can be effected using a transition metal catalyst such as palladium acetate, in the presence of an appropriate base, in an amide solvent such as N,N-dimethylformamide, at a temperature range of 20 to 150xc2x0 C. for 0.5 to 120 hours. When a boric-acid-substituted aryl group is contained in the structure of Q1 of the compound represented by the formula (Ib), coupling reaction of the compound with a halogen- or trifluoromethanesulfonyloxy-substituted aryl derivative or a halogen- or trifluoromethanesulfonyloxy-substituted alkenyl derivative can be effected. When a halogen- or trifluoromethanesulfonyloxy-substituted aryl group is contained in the structure of Q1 of the compound represented by the formula (Ib), coupling reaction of the compound with an alkenyl compound can be effected using a transition metal catalyst.
If the nitrogen atom of Q3b of the compound represented by the formula (Ib) has been protected as described above, the compound of the formula (Ia) can be obtained by deprotection as needed.
 less than Synthesis of the Compound Represented by the Formula (IIa) greater than 
The sulfonic acid halide of the formula (IIa) can be synthesized by any one of the various conventionally-reported processes (The Chemistry of Sulfonic Acids Esters and their Derivatives, Edited by S. Patai and Z. Rappoport, 1991, John Wiley and Sons Ltd.), for example, halogenation of the corresponding sulfonic acid of the following formula (IIb): 
or halogenosulfonylation of an unsaturated-bond-containing compound represented by the following formula (IIc): 
[wherein in the above formulas (IIb) and (IIc), R1, R2, R3, R4, R5, X1 and X2 have the same meanings as described above].
For example, the sulfonic acid halide of the formula (IIa) can be obtained by reacting the sulfonic acid of the formula (IIb) with a thionyl halide in the presence of N,N-dimethylformamide at 0 to 150xc2x0 C. for 0.5 to 24 hours. At this time, the reaction system can be diluted with a solvent such as dichloromethane, chloroform, carbon tetrachloride, N-methylpyrrolidin-2-one, dimethylsulfoxide or sulfolane.
The sulfonic acid halide of the formula (IIa) can also be obtained by reacting the unsaturated-bond-containing compound of the formula (IIc) with a thionyl halide or chlorosulfonic acid in a solvent such as N,N-dimethylformamide at 0 to 150xc2x0 C. for 0.5 to 24 hours.
The compound of the formula (I) can be obtained generally by reacting the compound of the formula (Ia), which has been synthesized by the above-described process or the like, with the sulfonic acid halide of the formula (IIa) which has been synthesized by the above-described process or the like, in the presence of an appropriate base, in an inert solvent at xe2x88x9278 to 150xc2x0 C.
Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium botoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane and acetone.
[Preparation Process-1-(1)]
When the nitrogen atom of Q3a of the compound represented by the formula (Ia), which is to be sulfonylated, exists as a primary or secondary amine, preferred examples of the base include carbonates and hydroxides of an alkali metal or an alkaline earth metal such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU) and usable examples of the solvent include, in addition to inert solvents, alcohol solvents such as ethanol and butanol and ester solvents such as ethyl acetate.
[Preparation Process-1-(2)]
When the nitrogen atom of Q3 of the compound represented by the formula (Ia), which is to be sulfonylated, forms an amide group, preferred examples of the base include alkoxides and hydrides of an alkali metal or an alkaline earth metal such as sodium ethoxide, potassium botoxide, sodium hydride and potassium hydride, organic metal bases typified an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide and organic bases such as diazabicyclo[5.4.0]undec-7-ene (DBU). Examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, dioxane and N,N-dimethylformamide.
[Preparation Process-2]
A process for preparing the sulfonyl derivative (I) by acylating the nitrogen atom of Q3a of the compound represented by the formula (VIIIa): 
[wherein R1, R2, R3, R4, R5, X1, X2, and Q3a have the same meanings as described above] with a carboxylic acid of the following formula (IVa):
Q1xe2x80x94Q2xe2x80x94COOHxe2x80x83xe2x80x83(IVa)
[wherein Q1 and Q2 have the same meanings as described above] or the carboxylic acid in an activated form.
The compound of the following formula (VIIIb): 
[wherein R1, R2, R3, R4, R5, X1, X2, and Q3b have the same meanings as described above] can be obtained by sulfonylating the nitrogen atom of the primary amine, secondary amine or amide compound of the formula (IIIa) with a sulfonic acid halide represented by the following formula (IIa): 
[wherein R1, R2, R3, R4, R5, X1, X2, and Halo have the same meanings as described above] in the presence of an appropriate base in an inert solvent at xe2x88x9278 to 150xc2x0 C.
Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane and acetone.
If the nitrogen atom of Q3b of the resulting compound represented by the formula (VIIIb) has been protected, the compound of the formula (VIIIa) can be obtained by deprotection as needed.
The compound of the formula (VIIIa) can be obtained by removing the protecting group of the nitrogen atom from the compound represented by the following formula (VIIIc): 
[wherein R2, R3, R4, R5, X1 and X2 have the same meanings as described above and Q3c represents any one of the following groups: 
(wherein
R22 represents a hydrogen atom,
an alkyl group,
a hydroxyl group protected with methoxymethyl, tetrahydropyranyl or the like,
a hydroxyalkyl group protected with methoxymethyl, tetrahydropyranyl or the like,
an alkoxyl group,
an alkoxyalkyl group ,
a dialkoxyalkyl group,
a dialkylamino group,
a monoalkylamino group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminoalkyl group,
a monoalkylaminoalkyl group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminocarbonyl group,
a dialkylaminocarbonylalkyl group,
a dialkylaminoalkyloxy group,
a monoalkylaminoalkyloxy group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminoalkylalkyloxy group,
a monoalkylaminoalkyloxy group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminocarbonylalkyloxy group or the like.
When the carbon atom to which R23, R24, R25 or R26 has been bonded is not adjacent to the nitrogen atom, R23, R24, R25 and R26 each independently represents:
a hydrogen atom,
an alkyl group,
a hydroxyl group protected with methoxymethyl, tetrahydropyranyl or the like,
a hydroxyalkyl group protected with methoxymethyl, tetrahydropyranyl or the like,
an alkoxyl group,
an alkoxyalkyl group,
a dialkoxyalkyl group,
a dialkylamino group,
a monoalkylamino group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminoalkyl group,
a monoalkylaminoalkyl group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminocarbonyl group,
a dialkylaminocarbonylalkyl group,
a dialkylaminoalkyloxy group,
a monoalkylaminoalkyloxy group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminocarbonylalkyloxy group or the like.
When the carbon atom to which R23, R24, R25or R26 has been bonded is adjacent to the nitrogen atom, R23, R24, R25 and R26 each independently represents:
a hydrogen atom,
an alkyl group,
a hydroxyalkyl group in which the hydroxyl moiety has been protected with methoxymethyl, tetrahydropyranyl or the like,
an alkoxyalkyl group,
a dialkoxyalkyl group,
a dialkylaminoalkyl group,
a monoalkylaminoalkyl group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminocarbonyl group,
a dialkylaminocarbonylalkyl group,
a dialkylaminoalkyloxy group or the like.
R23 and R24, as well as R25 and R26, may be coupled together to form a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent.
R27 represents:
an alkyl group,
a hydroxyalkyl group in which the hydroxyl moiety has been protected,
a hydroxyalkylcarbonyl group in which the hydroxyl moiety has been protected,
a hydroxyalkylsulfonyl group in which the hydroxyl moiety has been protected,
an alkoxyalkyl group,
an alkoxyalkylcarbonyl group,
an alkoxyalkylsulfonyl group,
an alkylcarbonyl group,
an alkylcarbonylalkyl group,
an alkylsulfonyl group,
an alkylsulfonylalkyl group,
an alkoxycarbonyl group,
an alkoxycarboylalkyl group,
an alkoxycarbonylalkylcarbonyl group,
an alkoxycarbonylalkylsulfonyl group,
a dialkylaminoalkyl group,
a monoalkylaminoalkyl group in which the amino moiety has been protected with tertiary butoxycarbonyl,
a dialkylaminocarbonyl group,
a dialkylaminocarbonylalkyl group, or the like.
R25 and R27, or R26 and R27 may be coupled together to form a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent.
R28 represents a tertiary butoxycarbonyl, benzyl or triphenylmethyl group, j and k each independently represents an integer of 0 or 1 and l stands for an integer of 1 to 3 with the proviso that the sum of k and l stands for an integer of 1 to 4.)]
The compound represented by the formula (VIIIc) can be obtained by reacting an amino compound which is available by the known process or application thereof and is represented by the following formula (IIIb):
Q3cxe2x80x94Hxe2x80x83xe2x80x83(IIIb)
[wherein Q3c has the same meaning as described above] with an alkylsulfonic acid halide in the presence of an appropriate base; reacting the resulting sulfonamide represented by the following formula (IXa): 
[wherein R3 and Q3c have the same meanings as described above] with a carbonyl compound represented by the following formula (XIa): 
[wherein R2, R4, R5, R22, X1 and X2 have the same meanings as described above ] in an inert solvent in the presence of an appropriate base to obtain the alcohol product represented by the following formula (XIIa): 
[wherein R2, R3, R4, R5, R22, Q3c, X1 and X2 have the same meanings as described above]; converting the alcohol moiety of the alcohol product (XIIa) into a methanesulfonyloxy group or the like in the presence of an appropriate base, or converting the alcohol moiety into a halogen atom by a phosphorus halide or triphenylphosphine/carbon tetrahalide, thereby forming an eliminating group; and then eliminating methanesulfonic acid or hydrogen halide in the presence of an appropriate base.
The sulfonamide compound of the formula (IXa) can be obtained by reacting the amino compound of the formula (IIIb) available by the known method or application thereof with an alkylsulfonic halide which may have a substituent, in the presence of an appropriate base, in an inert solvent at xe2x88x9278 to 150xc2x0 C.
Examples of the base include carbonates of an alkali metal or alkaline earth metal, such as sodium carbonate and potassium carbonate and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU). Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one. Dimethylsulfoxide, sulfolane, acetone or the like can be used, though depending on the kind of the bases employed.
The alcohol compound of the formula (XIIa) can be obtained by reacting the sulfonamide of the formula (IXa) with a carbonyl compound of the formula (XIa) in the presence of an appropriate base in an inert solvent at xe2x88x9278 to 110xc2x0 C.
Examples of the base include hydrides of an alkali metal or alkaline earth metal such as sodium ethoxide, potassium botoxide, sodium hydride and potassium hydride and organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide. Examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane and dioxane.
The compound of the formula (VIIIc) can be obtained by treating the hydroxyl group of the alcohol product of the formula (XIIa) with a phosphorus halide such as phosphorus pentachloride or a triphenylphosphine-halogen complex such as triphenylphosphine dibromide in the presence of an appropriate base, for example, the carbonate of an alkali metal or alkaline earth metal, such as sodium carbonate or potassium carbonate, or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene or N,N-dimethylformamide at xe2x88x9220 to 110xc2x0 C., thereby obtaining the corresponding halide, and then eliminating the hydrogen halide from the resulting halide under basic conditions, for example, by treating at xe2x88x9278 to 150xc2x0 C. with a carbonate, alkoxide, hydroxide or hydride of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, an organic metal base typified by alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide, or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.
The compound of the formula (VIIIc) can also be obtained by treating the hydroxyl group of the alcohol product represented by the formula (XIIa) with an alkyl- or arylsulfonic acid chloride such as methanesulfonic acid chloride in the presence of an appropriate base, for example, a carbonate of an alkali metal or alkaline earth metal such as sodium carbonate or potassium carbonate or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene or N,N-dimethylformamide at xe2x88x9220 to 110xc2x0 C. to obtain the corresponding alkyl- or arylsulfonate derivative; and then eliminating the alkyl- or arylsulfonic acid from the resulting alkyl- or arylsulfonate derivative under basic conditions, described specifically, by treating the resulting alkyl- or arylsulfonate derivative at xe2x88x9278 to 150xc2x0 C. in the presence of a carbonate, alkoxide, hydroxide or hydride of an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, an organic metal base typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide, or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU) in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.
The compound of the formula (VIIIc) can also be obtained by treating the sulfonamide of the formula (IXa) with a silyl halide such as trimethylsilyl chloride in the presence of an appropriate base in an inert solvent to convert it to the corresponding silyl compound, reacting the resulting silyl compound with a carbonyl compound of the formula (XIa) in the presence of a base in an inert solvent and then treating the reaction product under acidic to basic aqueous conditions (Peterson""s reaction). Described specifically, the compound of the formula (VIIIc) can be obtained by treating the sulfonamide of the formula (IXa) with an alkylsilyl chloride such as trimethylsilyl chloride at xe2x88x9278 to 110xc2x0 C. in the presence of a hydroxide of an alkali metal or alkaline earth metal such as sodium ethoxide, potassium butoxide, sodium hydride or potassium hydride or an organic metal base typified by an alkyl lithium such as n-butyl lithium or a dialkylamino lithium such as lithium diisopropylamide in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, to convert it to the corresponding silyl compound, condensing with the carbonyl compound of the formula (XIa) under the same conditions and then treating the condensate under acidic to basic aqueous conditions.
The protecting group for the nitrogen atom of the compound represented by the formula (VIIIc) can be removed by the ordinarily employed method. Described specifically, when the protecting group is a tertiary butoxycarbonyl group, it can be removed by using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid or combination thereof. The arylmethyl group such as benzyl can be removed by the hydrogenolysis in the presence of a palladium-carbon catalyst. The triphenylmethyl group can be removed by using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid or combination thereof. It can also be removed by Birch reduction with a metal sodium in liquid ammonia or by hydrogenolysis in the presence of a palladium-carbon catalyst.
Thus, by the removal of the protecting group from the compound of the formula (VIIIc), the compound of the formula (VIIIa) can be obtained. Examples of the carboxylic acid of the formula (IVa) in an appropriate activated form include mixed acid anhydrides available by reacting the carboxylic acid of the formula (IVa) with a chloroformate ester such as isobutyl chloroformate, thereby converting it into the corresponding acid anhydride, acid halides such as acyl chloride prepared by treating with an inorganic acid halide such thionyl chloride, active esters obtained by reacting with a phenol such as paranitrophenol or pentafluorophenyl-trifluoroacetate, active esters obtained by reacting it with N-hydroxybenztriazole or N-hydroxysuccinimide, reaction products with N,Nxe2x80x2-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride which is ordinarily employed in the synthesis of an amino acid, reaction products with diethyl cyanophosphonate (Shioiri""s method) and reaction products with triphenylphosphine and 2,2xe2x80x2-dipyridylsulfide (Mukaiyama""s method).
The resulting carboxylic acid in an activated form is then reacted with the compound of the formula (VIIIa) at xe2x88x9278xc2x0 C. to 150xc2x0 C., generally in the presence of an appropriate base in an inert solvent, whereby the sulfonyl derivative of the formula (I) can be obtained.
Specific examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane and acetone.
[Preparation Process-2-(1)]
When the nitrogen atom of Q3 of the compound of the formula (VIIIa): 
[wherein R1, R2, R3, R4, R5, X1, X2 and Q31 have the same meanings as described above] which is to be acylated exists as a primary or secondary amine, preferred examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU); and examples of the solvent include, in addition to inert solvents, alcohol solvents such as ethanol and butanol and ester solvents such as ethyl acetate.
[Preparation Process-2-(2)]
When the nitrogen atom of Q3 of the compound of the formula (VIIIa): 
[wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings as described above] which is to be acylated forms an amide bond, examples of the base include alkoxides and hydrides of an alkali metal or alkaline earth metal such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide and organic bases such as diazabicyclo[5.4.0]undec-7-ene (DBU) and preferred examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, dioxane and N,N-dimethylformamide.
[Preparation Process-3]
A process for preparing the sulfonyl derivative of the present invention, in the case where the nitrogen atom of Q3a of the compound represented by the following formula (VIIIa): 
[wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings as described above] forms an amide, by alkylating the nitrogen atom of the compound represented by the formula (VIIIa) with the compound represented by any one of the following formulas (Va) to (Vd).
Q1xe2x80x94Q2bxe2x80x94CHL1R18xe2x80x83xe2x80x83(Va)
xe2x80x83Q1xe2x80x94N(R20)xe2x80x94(CH2)m1xe2x80x94CHL1R18xe2x80x83xe2x80x83(Vb)
Q1xe2x80x94Oxe2x80x94(CH2)m1xe2x80x94CHL1R18xe2x80x83xe2x80x83(Vc)
Q1xe2x80x94Sxe2x80x94(CH2)m1xe2x80x94CHL1R18xe2x80x83xe2x80x83(Vd)
[wherein Q1, Q2b, R18, R20, ml and L1 have the same meanings as described above].
When the nitrogen atom of Q3a of the compound represented by the formula (VIIIa) forms an amide bond, the sulfonyl derivative of the formula (I) can be synthesized by alkylating the nitrogen atom with the compound of any one of the formulas (Va) to (Vd), described specifically, by reacting the compound of the formula (VIIIa) with the compound of any one of the formulas (Va) to (Vd) at xe2x88x9278 to 150xc2x0 C. in the presence of an appropriate base in an inert solvent for 0.5 to 120 hours, thereby alkylating the nitrogen atom.
Examples of the base include alkoxides and hydrides of an alkali metal or alkaline earth metal such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide and organic bases such as diazabicyclo[5.4.0]undec-7-ene (DBU). Preferred examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, toluene, dioxane and N,N-dimethylformamide.
[Preparation Process-4]
A process of preparing the sulfonyl derivative (I), in the case where the nitrogen atom of Q3 of the compound represented by the following formula (VIIIa): 
[wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings as described above] exists as a primary or secondary amine, by forming the corresponding imine with the carbonyl compound of any one of the following formulas (VIa) to (VId):
Q1xe2x80x94Q2bxe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VIa)
Q1xe2x80x94N(R20)xe2x80x94(CH2)m1xe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VIb)
Q1xe2x80x94Oxe2x80x94(CH2)m1xe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VIc)
Q1xe2x80x94Sxe2x80x94(CH2)m1xe2x80x94C(xe2x95x90O)R18xe2x80x83xe2x80x83(VId)
[wherein Q1, Q2b, R18, R20 and m1 have the same meanings as described above], followed by reduction.
When the nitrogen atom of Q3a of the compound of the formula (VIIIa) exists as an amine, the sulfonyl derivative of the formula (I) can be obtained by reacting the compound of the formula (VIIIa) with the carbonyl compound of any one of the formulas (VIa) to (VId) at xe2x88x9220 to 150xc2x0 C. for 0.5 to 120 hours generally in an inert solvent and if necessary in the presence of an organic acid such as acetic acid, mineral acid such as hydrochloric acid or Lewis acid such as aluminum chloride, thereby forming the corresponding imine; and hydrogenating the resulting imine at 10 to 110xc2x0 C. for 0.5 to 120 hours in an inert solvent in the presence of a boron hydride reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride or a catalytic reduction catalyst such as palladium-carbon.
Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide and sulfolane.
[Preparation Process-5]
A process of making use of the reaction wherein a urea derivative is formed by reacting, when Q3a of the compound of the following formula (VIIIa): 
[wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings as described above] exists as a primary or secondary amine, the compound of the formula (VIIIa) with the primary-amine-containing compound of any one of the formulas (VIIa) to (VIId):
Q1xe2x80x94Q2xe2x80x94NH2xe2x80x83xe2x80x83(VIIa)
xe2x80x83Q1xe2x80x94N(R20)xe2x80x94(CH2)m2xe2x80x94NH2xe2x80x83xe2x80x83(VIIb)
Q1xe2x80x94Oxe2x80x94(CH2)m2xe2x80x94NH2xe2x80x83xe2x80x83(VIIc)
Q1xe2x80x94Sxe2x80x94(CH2)m2xe2x80x94NH2xe2x80x83xe2x80x83(VIId)
or the secondary-amine-containing compound of the formula (VIIe): 
[wherein in the above formulas, Q1, Q2b and R20 and m2 have the same meanings as described above and a group of the following formula: 
has the same meaning as described above] by using a reagent such as carbonyldiimidazole.
When Q3a of the compound represented by the formula (VIIIa) is an amine, the primary-amine-containing compound of any one of the formulas (VIIa) to (VIId) or the secondary-amine-containing compound of the formula (VIIe) and a reagent such as 1,1xe2x80x2-carbonyldiimidazole are reacted with the compound of the formula (VIIIa) to introduce it into the sulfonyl derivative of the formula (I) of the present invention which is an urea derivative.
The derivative can be synthesized by reacting the primary-amine-containing compound of any one of the formulas (VIIa) to (VIId) or the secondary-amine-containing compound of the formula (VIIe) and then the compound of the formula (VIIIa) successively with a reagent such as carbonyldiimidazole, if necessary, in the presence of a base in an inert solvent. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide and sulfolane. Among them, dichloromethane, tetrahydrofuran and toluene are preferred.
Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU). It is only necessary to effect the reaction within a temperature range of from xe2x88x9270xc2x0 C. to 110xc2x0 C.
[Preparation Process-6]
A process of preparing the urea-containing sulfonyl derivative of the formula (I), in the case where the nitrogen atom of Q3a of the compound represented by the following formula (VIIIa): 
[wherein R1, R2, R3, R4, R5, X1, X2 and Q3a have the same meanings as described above] exists as a primary or secondary amine, by reacting the amine of the formula (VIIIa) with a known isocyanate derivative (Q1xe2x80x94Q2bxe2x80x94Nxe2x95x90Cxe2x95x90O) [wherein Q1 and Q2b have the same meanings as described above] or an isocyanate prepared from the carboxylic acid of any one of the following formulas (Iva)-(Ivd):
Q1xe2x80x94Q2bxe2x80x94COOHxe2x80x83xe2x80x83(IVa)
Q1xe2x80x94N(R20)xe2x80x94(CH2)m1xe2x80x94COOHxe2x80x83xe2x80x83(IVb)
Q1xe2x80x94Oxe2x80x94(CH2)m1xe2x80x94COOHxe2x80x83xe2x80x83(IVc)
Q1xe2x80x94Sxe2x80x94(CH2)m1xe2x80x94COOHxe2x80x83xe2x80x83(IVd)
[wherein Q1, Q2b, R20 and ml have the same meanings as described above].
When Q3a of the compound represented by the formula (VIIIa) is an amine, the sulfonyl derivative of the formula (I) can be obtained by reacting the compound of the formula (VIIIa) with a known isocyanate derivative in an inert solvent at xe2x88x9220 to 100xc2x0 C. for 0.5 to 120 hours.
The isocyanate derivative can also be synthesized from the carboxylic acid of any one of the formulas (IVa) to (IVd), described specifically, by converting the carboxylic acid of any one of the formulas (IVa) to (IVd) into the corresponding acid halide by using thionyl chloride or oxalyl chloride, reacting the resulting acid halide with sodium azide in an inert solvent at a temperature range of from 0 to 60xc2x0 C. and then heating the reaction mixture; by reacting the carboxylic acid of the formula (IVa) with a chloroformate such as isobutyl chloroformate to obtain the corresponding mixed acid anhydride, reacting the resulting anhydride with sodium azide and then heating; or by introducing the carboxylic acid of any one of the formulas (IVa) to (IVd) into the corresponding hydrazide through an ester in an inert solvent such as tetrahydrofuran, chloroform or toluene at xe2x88x9220 to 110xc2x0 C., reacting the hydrazide with nitric acid or alkyl ester thereof, thereby introducing into the corresponding acylazide and then heating the acylazide at 20 to 150xc2x0 C. in a solvent such as chloroform, dichloroethane, toluene, xylene or N,N-dimethylformamide.
The sulfonyl derivative of the formula (I) can also be prepared by reacting the carboxylic acid of any one of the formulas (IVa) to (IVd) with diphenylphosphoryl azide in the presence of a base such as triethylamine, in an inert solvent at a temperature range of 10 to 100xc2x0 C. and then reacting the resulting compound with the amine of the formula (VIIIa).
[Preparation Example-7]
A process for synthesizing the sulfonyl derivative represented by the following formula (I): 
[wherein R1, R2, R3, R4, R5, Q1, Q2, Q3, T1, X1 and X2 have the same meanings as described above] by coupling reaction using a transition metal catalyst.
When the structure of Q1 of the sulfonyl derivative represented by the formula (I) contains a halogen- or trifluoromethanesulfonyloxy-substituted aryl group, or a halogen or trifluoromethanesulfonyl-substituted alkenyl group, coupling reaction with a boric-acid-substituted aryl compound can be effected in the presence of a transition metal catalyst.
When an alkenyl group is contained in the structure of Q1 of the sulfonyl derivative of the formula (I), coupling reaction can be effected with a halogen- or trifluoromethanesulfonyloxy-substituted aryl group in the presence of a transition metal catalyst.
When a boric-acid-substituted aryl group is contained in the structure of Q1 of the sulfonyl derivative of the formula (I), coupling reaction can be effected with a halogen- or trifluoromethanesulfonyloxy-substituted aryl compound or a halogen- or trifluoromethanesulfonyloxy-substituted alkenyl compound.
When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), a halogen- or trifluoromethanesulfonyloxy-substituted aryl group is contained, coupling reaction can be effected with an alkenyl compound in the presence of a transition metal catalyst, whereby the sulfonyl derivative of the formula (I) can be obtained. The sulfonyl derivative of the formula (I) so obtained is subjected to deprotection as needed, whereby the compound of the formula (Ia) can be obtained.
When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), a halogen- or trifluoromethanesulfonyloxy-substituted aryl group or a halogen- or trifluoromethanesulfonyloxy-substituted alkenyl group is contained, coupling reaction with a boric-acid-substituted aryl derivative can be effected using a transition metal catalyst such as tetrakis(triphenylphosphine) palladium (O), in a two-phase solvent such as benzene-water or toluene-water, an amide solvent such as N,N-dimethylformamide or an ether solvent such as tetrahydrofuran or dimethoxyethane, in the presence of a base such as sodium carbonate, sodium hydroxide, barium hydroxide, potassium phosphate or cesium carbonate at a temperature range of 20 to 150xc2x0 C. for 0.5 to 120 hours.
When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), a boric-acid-substituted aryl group is contained, coupling reaction can be effected with a halogen- or trifluoromethanesulfonyloxy-substituted aryl compound or a halogen- or trifluoromethanesulfonyloxy-substituted alkenyl derivative.
When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), an alkenyl group is contained, coupling reaction can be effected with a halogen- or trifluoromethanesulfonyloxy-substituted aryl group by using a transition metal catalyst such as palladium acetate, in the presence of an appropriate base, in an amide solvent such as N,N-dimethylformamide at a temperature range of from 20 to 150xc2x0 C. for 0.5 to 120 hours.
When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), a boric-acid-substituted aryl group is contained, coupling reaction can be effected with a halogen- or trifluoromethanesulfonyloxy-substituted aryl derivative or a halogen- or trifluoromethanesulfonyloxy-substituted alkenyl derivative.
When in the structure of Q1 of the sulfonyl derivative represented by the formula (I), a halogen- or trifluoromethanesulfonyloxy-substituted aryl group, coupling reaction can be effected with an alkenyl compound by using a transition metal catalyst, whereby the sulfonyl derivative of the formula (I) can be obtained. From the sulfonyl derivative of the formula (I) so obtained, the sulfonyl derivative of the formula (I) with a changed substituent can be obtained by deprotection as needed.
[Preparation Process-8]
A process for preparing an amidoxime type sulfonamide product:
When T1xe2x80x94Q3 of the sulfonyl derivative represented by the following formula (I): 
[wherein R1, R2, R3, R4, R5, Q1, Q2, Q3, T1, X1 and X2 have the same meanings as described above] represents any one of the following formulas: 
[wherein R8, R9, R12, R13 and R14 have the same meanings as described above, n stands for an integer of 1 or 2, p stands for an integer of 1 to 3 and q stands for an integer of 0 to 3 with the proviso that the sum of p and 1 stands for an integer of 3 or 4] and none of amine-, alkylamine-, amido-, hydroxyl- and carboxylic-acid-containing substituents exist on R1, Q1 or Q2, or R8, R9, R12, R13 or R14 of Q3, or a substituent replaceable therewith, the sulfonyl derivative of the formula (I) is reacted with a halogenating agent such as phosphorus pentachloride or an alkylating agent such as Meerwein reagent in an inert solvent at xe2x88x9230 to 140xc2x0 C., preferably, in a halogen solvent such as chloroform at 0 to 80xc2x0 C. to obtain the corresponding imino chloride or imino ether and then the resulting imino chloride or imino ether is reacted with hydroxylamine, alkoxyamine which may have a substituent or salt thereof at 0 to 80xc2x0 C., preferably at 20 to 60xc2x0 C., if necessary in the presence of a base catalyst, whereby the target sulfonyl derivative of the formula (I) can be obtained.
Examples of the inert solvent include alkyl halide solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane and aromatic solvents such as benzene and toluene. Among them, the alkyl halide solvents are particularly preferred. Examples of the base include carbonates, alkoxides, hydroxides and hydrides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride; organic metal bases typified by an alkyl lithium such as n-butyl lithium and a dialkylamino lithium such as lithium diisopropylamide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
[Preparation Process-9]
N-oxide Formation
When in the sulfonyl derivative of the formula (I), there exists a nitrogen-containing heterocyclic aromatic ring or aliphatic tertiary amine on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, the sulfonyl derivative of the formula (I) is reacted with a peroxide such as hydrogen peroxide, metachloroperbenzoic acid or tertiary butyl hydroperoxide at xe2x88x9240 to 60xc2x0 C. for 0.5 to 120 hours preferably xe2x88x9220 to 20xc2x0 C. in water, acetic acid, a ketone solvent such as acetone, benzene solvent such as benzene, toluene or xylene, ether solvent such as tetrahydrofuran or dimethoxyethane or an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride, whereby the sulfonyl derivative of the formula (I) can be obtained as an N-oxide derivative.
[Preparation Process-10]
Quaternization of a Nitrogen Atom
When in the sulfonyl derivative of the formula (I), there exists a nitrogen-containing heterocyclic aromatic group or aliphatic tertiary amine on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, the sulfonyl derivative of the formula (I) is reacted with an alkyl halide such as methyl iodide or ethyl iodide in an ether solvent such as 1,2-dimethoxyethane or dioxane, an aromatic solvent such as benzene or toluene, an amide solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidin-2-one or a sulfoxide solvent such as dimethyl sulfoxide or sulfolane at xe2x88x9210 to 150xc2x0 C., preferably 0 to 80xc2x0 C., whereby the sulfonyl derivative of the formula (I) can be obtained as a quaternary amine product.
[Preparation Process-11]
Sulfoxide or Sulfone Formation
When in the sulfonyl derivative of the formula (I), a sulfur-containing hetero ring or aliphatic thioether exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, the sulfonyl derivative of the formula (I) is reacted with a peroxide such as hydrogen peroxide, metachloroperbenzoic acid or tertiary butyl hydroperoxide at xe2x88x9240 to 60xc2x0 C. for 0.5 to 120 hours, preferably xe2x88x9220 to 20xc2x0 C. in water, acetic acid, a ketone solvent such as acetone, a benzene solvent such as benzene, toluene or xylene, an ether solvent such as tetrahydrofuran or dimethoxyethane or an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride, whereby the sulfonyl derivative (I) can be obtained in the form of sulfoxide or sulfone.
[Preparation Process-12]
Amidino Formation-1
When in the sulfonyl derivative of the formula (I), a nitrile group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be converted into an amidino group by the ordinarily employed method. The amidino-containing sulfonyl derivative of the formula (I) can be obtained, for example, by allowing an equal amount to large excess of a C1-4 alcohol such as methanol, ethanol or propanol to act on the sulfonyl derivative of the formula (I) at xe2x88x9210 to 60xc2x0 C. for 3 to 120 hours in an aliphatic ether solvent such as diethyl ether, an alkyl halide solvent such as chloroform or dichloromethane or an aprotic solvent such as benzene or a mixed solvent thereof in the presence of a hydrogen halide such as hydrogen chloride or hydrogen bromide, thereby converting it to the corresponding imino ether; then reacting the resulting imino ether product with ammonium, a monoalkylamine which may have a substituent or a dialkylamine which may have a substituent or a carbonate or acetate thereof at xe2x88x9210 to 140xc2x0 C. for 0.5 to 200 hours in a C1-4 alcohol such as ethanol or propanol, an aliphatic ether solvent such as diethyl ether, an alkyl halide solvent such as chloroform, an aprotic solvent such as benzene, a solvent such as dimethylformamide or dimethylsulfoxide or a mixed solvent thereof, preferably at xe2x88x928 to 30xc2x0 C. for 10 to 96 hours in ethanol.
[Preparation Process-13]
Amidino Formation-2
When in the sulfonyl derivative of the formula (I), a primary or secondary amino group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be converted into a substituted amidino group by the ordinarily employed process.
Described specifically, the amidino-containing sulfonyl derivative of the formula (I) can be obtained by reacting the sulfonyl derivative of the formula (I) with an imino ether, imino chloride or salt thereof, which has been synthesized from an amide compound or nitrile compound, in an aliphatic ether solvent such as diethyl ether, an alkyl halide solvent such as chloroform or dichloromethane or an aprotic solvent such as benzene or a mixed solvent thereof, if necessary in the presence of a base catalyst, at xe2x88x9210 to 140xc2x0 C. for 0.5 to 200 hours, preferably 0 to 80xc2x0 C. for 10 to 96 hours. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
[Preparation Process-14]
N-nitrile Formation
When in the sulfonyl derivative of the formula (I), a primary or secondary amine group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be cyanated by the ordinarily employed process.
Described specifically, the sulfonyl derivative of the formula (I) is reacted with cyanogen bromide in an alcohol solvent such as methanol, ethanol or propanol in the presence. of a salt such as sodium acetate or a base at xe2x88x9210 to 110xc2x0 C., preferably 0 to 60xc2x0 C., whereby the sulfonyl derivative (I) having a nitrile group on its nitrogen atom can be obtained. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
[Preparation Process-15]
Amidoxime or Carboxamido-O-alkyloxime Introduction
When in the sulfonyl derivative of the formula (I), a nitrile group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be converted into an amidoxime or carboxamido-O-alkyloxime group by the ordinarily employed process.
Described specifically, the sulfonyl derivative of the formula (I) is reacted with hydroxylamine or an alkoxyamine which may have a substituent or salt thereof in an alcohol solvent such as methanol, ethanol or propanol, an ether solvent such as diethyl ether or tetrahydrofuran, a halogenated hydrocarbon such as chloroform or dichloromethane, an aprotic solvent such as toluene, an amide solvent such as N,N-dimethylformamide or a solvent such as dimethylsulfoxide or a mixed solvent thereof at xe2x88x9210 to 110xc2x0 C., preferably 0 to 60xc2x0 C., if necessary in the presence of a base catalyst, whereby the sulfonyl derivative of the formula (I) having an amidoxime or carboxamido-O-alkyloxime group can be obtained. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
[Preparation Process-16]
Guanidino Introduction
When in the sulfonyl derivative of the formula (I), a primary or secondary amino group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be converted into a substituted or unsubstituted guanidino group by the ordinarily employed process.
Described specifically, the sulfonyl derivative of the formula (I) having a primary or secondary amino group is reacted with N,Nxe2x80x2-di(tert-butoxy)carbonylthiourea by using as a condensing agent N,Nxe2x80x2-dicyclohexylcarbodiimide in an aliphatic ether solvent such as diethyl ether, a halogenated hydrocarbon such as chloroform or dichloromethane or an aprotic solvent such as benzene, or a mixed solvent thereof at xe2x88x9210 to 140xc2x0 C. for 0.5 to 200 hours, preferably 0 to 80xc2x0 C. for 10 to 96 hours, if necessary in the presence of a base catalyst, and then, as usual, the tertiary butoxycarbonyl group is removed, whereby the sulfonyl derivative of the formula (I) as a guanidino compound can be synthesized. Examples of the base include carbonates and hydroxides of an alkali metal or alkaline earth metal, such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; and organic bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo[5.4.0]undec-7-ene (DBU).
[Preparation Process-17]
Deprotection from the Protected Nitrogen Atom
When in the sulfonyl derivative of the formula (I), an acylamino or alkoxycarbonylamino group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, the derivative can be hydrolyzed at 0 to 80xc2x0 C. in a solvent such as water, a lower alcohol or tetrahydrofuran or a mixed solvent thereof in the presence of a base such as an alkali metal hydroxide e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide, whereby an amino-containing derivative can be obtained. The nitrogen atom to which an acyl type protecting group such as tertiary butoxycarbonyl or paramethoxybenzyloxycarbonyl has been bonded can be converted into a nitrogen-hydrogen bond by using an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid or combination thereof and removing the acyl type protecting group from the nitrogen atom at 0 to 80xc2x0 C. in an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane or an aromatic solvent such as benzene or toluene.
The nitrogen atom to which an arylmethoxycarbonyl group such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl or para(ortho)-nitrobenzyloxycarbonyl has been bonded can be converted into a nitrogen-hydrogen bond by removing the arylmethoxycarbonyl group from the protected nitrogen through hydrogenolysis in the presence of a palladium-carbon catalyst in a solvent such as ethanol, tetrahydrofuran, acetic acid or N,N-dimethylformamide. The nitrogen atom to which a silyl type protecting group such as trimethylsilyl or tertiary butyl dimethylsilyl has been bonded can be converted into a nitrogen-hydrogen bond by reacting with hydrochloric acid or a hydrofluoride such as tetrabutylammonium fluoride at 0 to 80xc2x0 C. in an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane or an aromatic solvent such as benzene or toluene, thereby removing the silyl group from the protected nitrogen atom. The nitrogen atom to which a benzyl group has been bonded can be converted into a nitrogen-hydrogen bond by removing the benzyl group through the catalytic reduction with a palladium-carbon catalyst or the like at 0 to 80xc2x0 C. in a solvent such as ethanol, tetrahydrofuran or acetic acid or through the Birch""s reduction with a metal sodium in a liquid ammonia. The nitrogen atom to which a triphenyl group has been bonded can be converted into a nitrogen-hydrogen bond by removing the triphenyl group through the catalytic reduction with a palladium-carbon catalyst or the like at 0 to 80xc2x0 C. in a solvent such as ethanol, tetrahydrofuran or acetic acid or through the Birch""s reduction with a metal sodium in a liquid ammonia. The removal of the triphenylmethyl group and conversion into a nitrogen-hydrogen bond can be carried out by using an appropriate acid, such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or trifluoromethanesulfonic acid or a combination thereof at 0 to 80xc2x0 C.
[Preparation Process-18]
Ester Hydrolysis
When in the sulfonyl derivative of the formula (I), an alkoxycarbonyl group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, the alkoxycarbonyl group protected in the methyl or ethyl ester form can be converted into the corresponding carboxylic acid by the hydrolysis with an appropriate base, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. In the case of the protection in the form of a tertiary butyl ester, the tertiary butyl group can be removed by treating with trifluoroacetic acid or hydrochloric acid, while in the case of the protection in the form of an arylmethyl type ester such as benzyl, the carboxylic acid can be obtained by removing the arylmethyl group by hydrogenolysis in the presence of a palladium-carbon catalyst.
[Preparation Process-19]
When in the sulfonyl derivative of the formula (I), an acyloxy, arylmethyloxy, silylether, methoxymethyl or tetrahydropyranyl group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, the acyl group such as alkanoyl or aroyl can be removed by the hydrolysis with an appropriate base, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The arylmethyl type protecting group can be removed by the hydrogenolysis with a palladium-carbon catalyst. The silylether group such as tertiary butyl dimethylsilyl can be removed by a salt of hydrofluoride such as tetrabutylammonium fluoride. The methoxymethyl or tetrahydropyranyl group can be removed by acetic acid or hydrochloric acid.
[Preparation Process-20]
When in the sulfonyl derivative of the formula (I), an amino group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be acylated by the ordinarily employed process which uses an acyl halide or carboxylic acid in an activated form. Alternatively, it can be alkylated by reductive alkylation or the like method. The sulfonyl derivative of the formula (I) which is an urea derivative can be prepared by sulfonylation through sulfonic acid chloride or by reacting with an isocyanate or an isocyanate derived from a carboxylic acid.
[Preparation Process-21]
When in the sulfonyl derivative of the formula (I), an carboxyl group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be converted into a carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group by the ordinarily employed active ester method or mixed acid anhydride method and then converted into a hydroxyl or aldehyde group by reduction. The resulting hydroxyl or aldehyde group can be subjected to conversion of a functional group, such as ether bond formation, conversion into an amino group or conversion into an alkylamino group by the process ordinarily employed in organic chemistry. The carboxyl group, after conversion into its ester or mixed acid anhydride directly or by the usual process, is reduced, whereby the corresponding alcohol can be obtained.
[Preparation-22]
Formation of Phenol
When in the sulfonyl derivative of the formula (I), an aryl-substituted methoxy group exists on R1, Q1, Q2, Q3 or T1 or a substituent replaceable therewith, it can be converted into a hydroxyl group by removing the methyl group using trimethylsilyl iodide in an alkyl halide solvent such as dichloromethane, chloroform or carbon tetrachloride or a benzene solvent such as toluene, a Lewis acid such as aluminum chloride or phosphorus tribromide, an alkyl halide solvent or an ether solvent at xe2x88x9278 to 110xc2x0 C.
The sulfonyl derivative of the formula (I) according to the present invention, salt thereof or solvate thereof has peculiar and excellent FXa inhibitory activity and is therefore useful as a coagulation suppressor or a preventive and/or remedy for thrombosis or embolism.
The sulfonyl derivative of the present invention exhibits effects even by the oral administration so that it can be administered either orally or parenterally. The dose of the sulfonyl derivative may be changed as needed depending on the symptom, age, weight and/or the like of a patient. It is necessary to administer the derivative in an amount of 1 to 1000 mg/day, preferably 5 to 300 mg/day per adult. Although no particular limitation is imposed on the dosage form, examples include tablets, capsules, powders, granules, suspensions, syrups and dry syrups. The derivative together with ordinarily employed additives such as excipient, lubricant or binder can be formulated into the above-described dosage forms in accordance with the known formulation technique.
No particular limitation is imposed on the dosage form in the case of parenteral administration but examples include ointments, plasters, injections and suppositories. As an injection, the derivative may be administered subcutaneously or intravenously or by intravenous drip in an amount of 0.1 to 100 mg/day, preferably 0.5 to 30 mg/day per adult.
The present invention will hereinafter be described more specifically by Referential Examples, Examples and Tests, but it should however be borne in mind that the present invention is not limited to or by them.